We might be looking at a cure for a major auto-immune disorder and the treatment might eventually work for other auto-immune diseases. Monoclonal antibody drug Alemtuzumab prevents M.S. recurrence in a substantial portion of patients.
A drug which was developed in Cambridge and initially designed to treat a form of leukaemia has also proven effective against combating the debilitating neurological disease multiple sclerosis (MS).
The study, led by researchers from the University of Cambridge, has found that alemtuzumab not only stops MS from advancing in patients with early stage active relapsing-remitting multiple sclerosis (RRMS) but may also restore lost function caused by the disease. The findings were published today in the New England Journal of Medicine.
Alemtuzumab has a long connection with Cambridge, England. In 1984, Cambridge scientist Cesar Milstein was awarded the Nobel Prize for Physiology or Medicine, jointly with George Kohler, for inventing the technology to make large quantities of a desired type of monoclonal antibody. Further work in Cambridge, by Herman Waldmann and Greg Winter, led to the production of the first humanised monoclonal antibody for use as a medicine, Campath-1H, now known as alemtuzumab. It has been licensed for the treatment of chronic lymphocytic leukaemia, and has also been tested in several diseases where the immune system is overactive, such as multiple sclerosis.
The new study, which was funded by Genzyme and Bayer Schering Pharma AG, Germany , found that alemtuzumab reduces the number of attacks experienced by people with relapsing-remitting multiple sclerosis by 74 per cent over and above that achieved with interferon beta-1a, one of the most effective licensed therapies for similar cases of MS. More importantly, alemtuzumab also reduced the risk of sustained accumulation of disability by 71 per cent compared to interferon beta-1a.
Additionally, the investigators showed that many individuals in the trial who received alemtuzumab recovered some of their lost functions and so were less disabled after three years than at the beginning of the study, in contrast to worsening disability in the interferon beta-1a treated patients. These findings suggest that alemtuzumab may allow damaged brain tissue to repair, enabling the recovery of neurologic functions lost following poor recovery from previous MS attacks.
One patient died from a complication (idiopathic thrombocytopenic purpura (ITP)) of the treatment. But now that the complication is known the hope is that it can be recognized sooner and better managed.
The drug works by wiping out lymphocytes. This has to cause problems with greater risk from infectious diseases. It is a rather broad wiping out since the drug doesn't have specificity for just those immune cells that are attacking the brain.
The treatment works by destroying all the patients' lymphocytes, the T-and B-cells that normally fight infections, but which mistakenly attack nerves and brain tissue in MS patients.
Following the treatment, the immune system grows back, but without the cells that cause MS. "It's as though you've re-booted the immune system, so it's better behaved," Coles says.
The whole process takes about three to four years, adds Coles, who is hopeful that the drug might also be able to help patients with other auto-immune diseases such as diabetes and lupus.
A more ideal auto-immune disease treatment would target only those immune cells attacking the body. But that's a much harder problem to solve than the problem of wiping out all T and B cells.
War, as tragic as it is, creates demands for regenerative therapies and the money to fund the research. A big push to develop regenerative therapies will incidentally help speed the development of rejuvenation therapies.
WINSTON-SALEM, N.C. – A consortium spearheaded by the Institute for Regenerative Medicine at Wake Forest University Baptist Medical Center has been awarded $42.5 million over five years to co-lead one of two academic groups that will form the Armed Forces Institute of Regenerative Medicine (AFIRM).
Anthony Atala at Wake Forest already leads a big effort in tissue engineering to develop replacement organs. His team and collaborators at other universities will work on regenerative medicine techniques. These techniques used on young maimed soldiers will also some day work on old age-ravaged bodies.
The consortiums, working with the U.S. Army Institute of Surgical Research, will use the science of regenerative medicine to develop new treatments for wounded soldiers.
The Wake Forest-led collaboration will be headed by Anthony Atala, M.D., director of the Wake Forest Institute for Regenerative Medicine, and Alan J. Russell, Ph.D., director of the McGowan Institute for Regenerative Medicine at the University of Pittsburgh. A second consortium will be managed by Rutgers and the Cleveland Clinic.
AFIRM will be dedicated to repairing battlefield injuries through the use of regenerative medicine, science that takes advantage of the body’s natural healing powers to restore or replace damaged tissue and organs. Therapies developed by AFIRM will also benefit people in the civilian population with burns or severe trauma.
"For the first time in the history of regenerative medicine, we have the opportunity to work at a national level to bring transformational technologies to wounded soldiers, and to do so in partnership with the armed services," said Atala. "This field of science has the potential to significantly impact our ability to successfully treat major trauma."
The Wake Forest-University of Pittsburgh team has committed to develop clinical therapies over the next five years that will focus on the following five areas:
- Burn repair
- Wound healing without scarring
- Craniofacial reconstruction
- Limb reconstruction, regeneration or transplantation
- Compartment syndrome, a condition related to inflammation after surgery or injury that can lead to increased pressure, impaired blood flow, nerve damage and muscle death.
AFIRM will have multiple groups working in each area. For example, in the area of burns, researchers will pursue treatments including engineered skin products, bio-printing of skin in the field and repairs using stem cells derived from amniotic fluid.
Engineered skin products will also some day replace aged skin. Tissue engineering to grow replacement bone will also work for aged joints and bones.
Even if research specifically aimed at rejuvenation and life extension was banned all the efforts to develop regenerative therapies for younger maimed and scarred bodies would provide the tools needed to do rejuvenation anyway. The difference between regeneration and rejuvenation is slight.
Lots of liver diseases kill by causing accumulation of scar tissue. Well, at least in mice the scarring process can be stopped and partially reversed with an inhibitor peptide.
University of California, San Diego researchers have proven in animal studies that fibrosis in the liver can be not only stopped, but reversed. Their discovery, to be published in PLoS Online on December 26, opens the door to treating and curing conditions that lead to excessive tissue scarring such as viral hepatitis, fatty liver disease, cirrhosis, pulmonary fibrosis, scleroderma and burns.
Six years ago, the UC San Diego School of Medicine research team discovered the cause of the excess fibrous tissue growth that leads to liver fibrosis and cirrhosis, and developed a way to block excess scar tissue in mice. At that time, the best hope seemed to be future development of a therapy that would prevent or stop damage in patients suffering from the excessive scarring related to liver or lung disease or severe burns.
In their current study, Martina Buck, Ph.D., assistant professor of medicine at UCSD and the Veterans Affairs San Diego Healthcare System, and Mario Chojkier, M.D., UCSD professor of medicine and liver specialist at the VA, show that by blocking a protein linked to overproduction of scar tissue, they can not only stop the progression of fibrosis in mice, but reverse some of the cell damage that already occurred.
We have been watching bioscience and biotechnological advances for many years. Isn't it about time this progress starts to translate into a whole bunch of disease cures? It is all well and good to watch the progress and marvel at the cleverness of the researchers who find ways to tease out the secrets of biological systems. But getting down to some curing treatments would be great. You might want to see cancer or heart disease cured first. But I'd be happy to see an end to death by liver cirrhosis as a starter.
Inhibition of a protein that actives growth of a type of cell involved in collagen production did the trick.
In response to liver injury – for example, cirrhosis caused by alcohol – hepatic stellate cell (HSC) activated by oxidative stress results in large amounts of collagen. Collagen is necessary to heal wounds, but excessive collagen causes scars in tissues. In this paper, the researchers showed that activation of a protein called RSK results in HSC activation and is critical for the progression of liver fibrosis. They theorized that the RSK pathway would be a potential therapeutic target, and developed an RSK inhibitory peptide to block activation of RSK.
The scientists used mice with severe liver fibrosis – similar to the condition in humans with cirrhosis of the liver – that was induced by chronic treatment with a liver toxin known to cause liver damage. The animals, which continued on the liver toxin, were given the RSK-inhibitory peptide. The peptide inhibited RSK activation, which stopped the HSC from proliferating. The peptide also directly activated the caspase or “executioner" protein, which killed the cells producing liver cirrhosis but not the normal cells.
“All control mice had severe liver fibrosis, while all mice that received the RSK-inhibitory peptide had minimal or no liver fibrosis,” said Buck.
Researchers probably had to spend many years teasing out the connection between the RSK protein, hepatic stellate cells, collagen production and scar tissue accumulation. But now they have something really powerful to show for it. Hurray.
But how many years will it take for a human treatment to make it to market?
Nicotinamide (aka niacinamide as distinct from niacin) is the form of vitamin B3 that does not cause flushing in your skin. Nicotinamide injected into mice provided protection to nerve cells from a mouse disease that is very similar to multiple sclerosis.
A team led by Shinjiro Kaneko, MD, a research fellow at Children's, and senior investigator Zhigang He, PhD, also from Children's, worked with mice that had an MS-like disease called experimental autoimmune encephalitis (EAE). Through careful experiments, they showed that nicotinamide protected the animals' axons from degeneration - not only preventing axon inflammation and myelin loss, but also protecting axons that had already lost their myelin from further degradation.
Intriguingly, mice with EAE who received daily nicotinamide injections under their skin had a delayed onset of neurologic disability, and the severity of their deficits was reduced for at least eight weeks after treatment. The greater the dose of nicotinamide, the greater the protective effect.
This is great news because nicotinamide has very low toxicity, is cheap, and is easy to administer. Just taking large doses in pills might be enough to greatly slow the progress of MS.
The highest nicotinamide doses provided the biggest benefit.
On a scale of 1 to 5 (1 indicating mild weakness only in the tail, 4 indicating paralysis involving all four limbs, and 5, death from the disease), mice receiving the highest doses of nicotinamide had neurologic scores between 1 and 2, while control mice had scores between 3 and 4. All differences between treated groups and controls were statistically significant.
Mice with the greatest neurologic deficits had the lowest levels of NAD in their spinal cord, and those with the mildest deficits had the highest NAD levels. Mice that had higher levels of an enzyme that converts nicotinamide to NAD (known as Wlds mice) responded best to treatment.
Moreover, nicotinamide significantly reduced neurologic deficits even when treatment was delayed until 10 days after the induction of EAE, raising hope that it will also be effective in the later stages of MS. 'The earlier therapy was started, the better the effect, but we hope nicotinamide can help patients who are already in the chronic stage,' says Kaneko.
In other experiments, the researchers demonstrated that nicotinamide works by increasing levels of NAD in the spinal cord and that NAD levels decrease when axons degenerate. Finally, they showed that giving NAD directly also prevented axon degeneration.
NAD is used extensively by cells to produce energy through the breakdown of carbohydrates.
Perhaps nicotinamide works by boosting energy output so that damaged nerve cells can repair themselves faster and thereby avoid too much accumulated damage.
As much as I like high technology I even more like low tech solutions that can be put into practice immediately.
If you are wondering about dosing: The doses were 125 mg per kg and 500 mg per kg. A kilogram is 2.2 pounds. I have no idea whether the human doses would need to scale by those ratios.
CHAPEL HILL - Scientists from the University of North Carolina at Chapel Hill have established how statins -- cholesterol-lowering drugs -- inhibit inflammation and nerve cell damage caused by multiple sclerosis.
Preliminary research has shown that multiple sclerosis (MS) patients taking statins with their standard drug regimen develop less nerve cell damage over time than MS patients on standard therapy. Understanding the precise mechanisms by which statins fight multiple sclerosis is an important step toward approving the commonly used drugs for MS treatment, said Dr. Silva Markovic-Plese, associate professor of neurology, immunology and microbiology in the UNC School of Medicine.
In tests performed on blood samples from people with relapse-remitting MS, statins shut down several inflammatory processes. The statins inhibited the formation of immune-system cells called lymphocytes and monocytes, which cause inflammation by attacking the body's nerve cells.
"When we compared the effects of statins to well-understood MS therapies such as interferon, an anti-inflammatory, statins were equal if not stronger in some aspects," Markovic-Plese said. The researchers also examined blood samples from healthy people.
People suffering from MS ought to consider taking one of the statin drugs such as Crestor (Rosuvastatin), Lipitor (Atorvastatin), Zocor (Simvastatin), Mevacor (Lovastatin), Pravachol (Pravastatin), or Lescol (Fluvastatin).
Presbyopia---the inability to focus on close objects resulting in blurred vision---affects 100 percent of people by age 50. Historically, laser correction of the intraocular lens for presbyopia has been proposed, but it is risky because there is no way to monitor the procedure---no way for ophthalmologists to see what they are doing to the lens being cut.
But a tool developed at the University of Michigan allows for a potentially noninvasive, painless fix to presbyopia using tiny bubbles that help ophthalmologists reshape the eye’s lens and restore its flexibility and focusing ability. Matthew O’Donnell, professor and chair of the U-M Department of Biomedical Research, along with Kyle Hollman, assistant research scientist and adjunct lecturer, and graduate student Todd Erpelding, developed the method. Recently, it was successful when tested in pig lenses.
Presbyopia usually starts around age 40, O’Donnell saays. The predominant belief is that fibers created in the intraocular lens accumulate and stiffen, thus making the lens less flexible. Without that flexibility, the lens can’t change shape to focus on near objects, a process called accommodation.
So, while a young eye is like an automatic focus camera, the presbyopic eye can be thought of as a fixed focus camera, he says. One way to potentially solve presbyopia is to laser away some fibers to restore flexibility, but there is no way to know how much or where to cut, he adds.
“There are no noninvasive or minimally invasive procedures for presbyopia,” said O’Donnell, 55, who explained that he started research on presbyopia when he began to notice his own near-sight failing. He held up his reading glasses: “I got sick of wearing these things.”
The U-M tool uses bubbles, ultrafast optics and ultrasound to measure the thickness and rigidity of the lens during laser surgery, thus guiding the surgeon as they reshape the lens. It’s a new application for microscale bubbles, which scientists have experimented with for years in the areas of drug delivery, tumor destruction and other medical applications.
For the treatment of presbyopia, the U-M team used ultrafast laser pulses to create tiny gas bubbles within the intraocular lens. Before the bubbles diffuse, researchers hit them with high frequency sound waves, which push the bubbles against neighboring lens fibers.
“Part of the sound is reflected, and from the characteristic of the reflection, you know where the bubble is,” O’Donnell said. “It uses exactly the same technology as ultrasound imaging.”
In this way, researchers measure how far the bubbles have moved based on the force applied, and thus measure the pliability of the lens.
“The bubbles show you where the laser should cut,” O’Donnell said. “If it’s still too hard, you cut some more. If it’s soft enough, you stop.”
The future plan is to automate the procedure to quickly cover the entire lens with bubbles, he said. The team, which will begin testing this year, is talking with several companies about commercial opportunities.
Growth or synthesis of replacement lenses may also eventually solve this problem.
How will the world look differently 20 years from now? In industrialized countries corrective glasses will be rare, obesity will be rare, and baldness and even hair graying will be rare. What else do you think will be obviously different in a stroll down a city street in the year 2026?
Researchers at the University of Virginia Health System have made an exciting discovery: a combination of human-safe treatments reversed the course of Type 1 diabetes in mice. Using this model, the researchers found that a combined therapy of lisofylline (LSF) and exendin-4 (Ex-4) effectively reversed newly acquired Type 1 diabetes, also called autoimmune diabetes.
Dr. Jerry Nadler, chief of the UVa Division of Endocrinology and Metabolism, and colleagues theorized that simultaneously blocking a biological pathway that damages beta cells in the pancreas, while adding a growth-promoting stimulus for beta cells, might provide the critical ability to reverse Type 1 diabetes. "This finding is very exciting because it one day may provide an opportunity to restore insulin-producing cells in people with Type 1 diabetes without the need for toxic anti-rejection medications," Nadler said. Type 1 diabetes represents 5-10 percent of all diabetes cases diagnosed, and in the United States there may be 2 million people with Type 1 diabetes.
This treatment also helped the mice to return to and maintain normal, healthy levels of blood sugar. Even after treatment was stopped, blood sugar remained normal until the experiment was completed, as many as 145 days post-treatment. This is the first time that researchers have found a way to reverse diabetes by providing a combination treatment that also could help maintain normal levels of blood sugar in a mammalian model.
The research team used two treatments to reverse the course of diabetes in this model, according to their study, published online in Biochemical and Biophysical Research Communications. One treatment used in this study, lisofylline, suppresses certain immune cells that can destroy beta cells. Lisofylline also allows beta cells to keep producing insulin, as they normally would, even in the presence of destructive substances called cytokines that cause inflammation. In response to glucose stimulation, lisofylline helps the beta cells to enhance their insulin secretion. The second treatment was Exendin-4 (Ex-4), a potent substance that increases insulin secretion and helps the beta cells to grow.
These drugs can be tried for this purpose in humans:
“This treatment may someday benefit people with diabetes, because both LSF and Ex-4 have been tested in humans for other benefits and have been found to be safe,” Nadler said.
What stands in the way of trying this therapy in humans? Could both drugs be prescribed in the United States for off-label use now?
ATLANTA, GA (March 13, 2006) -- A study presented today at the American College of Cardiology's 55th Annual Scientific Session demonstrates, for the first time, that very intensive cholesterol lowering with a statin drug can regress (partially reverse) the buildup of plaque in the coronary arteries. This finding has never before been observed in a study using statin drugs, the most commonly used cholesterol lowering treatment. Previous research had indicated that intensive statin therapy could prevent the progression of coronary atherosclerosis, or arterial plaque build-up, but not actually reduce disease burden. ACC.06 is the premier cardiovascular medical meeting, bringing together more than 30,000 cardiologists to further breakthroughs in cardiovascular medicine.
The intense statin therapy used in this study resulted in significant regression of atherosclerosis as measured by intravascular ultrasound (IVUS), a technique in which a tiny ultrasound probe is inserted into the coronary arteries to measure plaque. The study showed that regression occurred for all three pre-specified IVUS measures of disease burden. The mean baseline LDL cholesterol of 130.4 mg/dL dropped to 60.8 mg/dL in the study patients, an reduction of 53.2 percent. This is the largest reduction in cholesterol ever observed in a major statin outcome trial. Mean HDL cholesterol (43.1 mg/dL at baseline) increased to 49.0 mg/dL, a 14.7 percent increase, which was also unprecedented. The arterial plaque overall was reduced by 6.8 to 9.1% for the various measures of disease burden.
This study was known by the acronym of ASTEROID (A Study To Evaluate the Effect of Rosuvastatin On Intravascular Ultrasound-Derived Coronary Atheroma Burden [ASTEROID] Trial). The trial was conducted at 53 community and tertiary care centers in the United States, Canada, Europe, and Australia. A total of 507 patients had baseline intravascular ultrasound (IVUS) examination and received 40 mg daily of rosuvastatin (brand name CrestorÂ®). IVUS provides a precise and reproducible method for determining the change in plaque, or atheroma, burden during treatment. Atherosclerosis progression was assessed at baseline and after at 24 months of treatment.
"Previous similar studies with statins have shown slowing of coronary disease, but not regression. This regimen significantly lowered bad cholesterol, and surprisingly, markedly increased good cholesterol levels," said Steven Nissen, M.D., F.A.C.C., of the Cleveland Clinic and lead author of the study. Dr. Nissen is also President-Elect of the American college of Cardiology. "We conclude that very low LDL levels (below current guidelines), when accompanied by raised HDL, can regress, or partially reverse, the plaque buildup in the coronary arteries."
I expect a continued drop in death from heart disease relative to the rate of death from cancer. Heart disease is relatively easier to avoid. To tackle cancer we need to get control of all the mechanisms by which cells control their division and spread. That's much harder than avoiding accumulation of junk in arteries. Another very encouraging but more preliminary report on the heart disease front just came out of Johns Hopkins where researchers found they can reverse cardiac hypertrophy in obese mice with hormones.
Working on genetically engineered obese mice with seriously thickened hearts, a condition call cardiac hypertrophy, scientists at Johns Hopkins have used a nerve protection and growth factor on the heart to mimic the activity of the brain hormone leptin, dramatically reducing the size of the heart muscle.
Leptin is a protein hormone made by fat cells that signals the brain to stop eating. Alterations in the leptin-making gene may create leptin deficiency linked to obesity and other defects in weight regulation.
By injecting so-called ciliary neurotrophic factor (CNTF) into mice that were either deficient in or resistant to leptin, the researchers reduced the animals' diseased and thickened heart muscle walls by as much as a third and the overall size of the left ventricle, the main pumping chamber, up to 41 percent, restoring the heart's architecture toward normal.M
Enlarged hearts lead to heart failure and death. Results of the study, supported in part by the National Institutes of Health, are to be published in the March 6 issue of the Proceedings of the National Academy of Sciences.
"These findings suggest there's a novel brain-signaling pathway in obesity-related heart failure and have therapeutic implications for patients with some forms of obesity-related cardiovascular disease," says study senior author Joshua M. Hare, M.D., a professor and medical director of the heart failure and cardiac transplantation programs at The Johns Hopkins University School of Medicine and its Heart Institute.
Ultrasound exams of the hearts after four weeks showed that CNTF decreased the thickness of the wall dividing the heart chambers by as much as 27 percent, decreased the thickness of the wall at the back of the heart by as much as 29 percent and overall volume of the left ventricle by as much as 41 percent.
Note that this study was done with mice. The result still needs confirmation in humans.
Jenkins and his colleagues prescribed a seven-day menu high in viscous fibres, soy protein, almonds and plant sterol margarine to 66 people -- 31 men and 35 women with an average age of 59.3 and within 30 percent of their recommended cholesterol targets. For the first time, 55 participants followed the menu under real-world conditions for a year. They maintained diet records and met every two months with the research team to discuss their progress and have their cholesterol levels measured.
"The participants found it easiest to incorporate single items such as the almonds and margarine into their daily lives," says Jenkins, who is also staff physician of endocrinology at St. Michael's Hospital. "The fibres and vegetable protein were more challenging since they require more planning and preparation, and because these types of niche products are less available. It's just easier, for example, to buy a beef burger instead of one made from soy, although the range of options is improving. We considered it ideal if the participants were able to follow the diet three quarters of the time."
After 12 months, more than 30 per cent of the participants had successfully adhered to the diet and lowered their cholesterol levels by more than 20 per cent. This rate is comparable to the results achieved by 29 of the participants who took a statin for one month under metabolically controlled conditions before following the diet under real-world conditions.
See my previous report on the Jenkins diet: "Ape Man Diet Lowers Cholesterol And Inflammation Marker"
"What's exciting is we may now be able to design a therapy that will seek out and destroy only cancer cells," said the study's senior author, Paul B. Fisher, Ph.D., professor of clinical pathology and Michael and Stella Chernow Urological Cancer Research Scientist at Columbia University Medical Center. "We hope it will be particularly powerful in eradicating metastases that we can't see and that can't be eliminated by surgery or radiation. Gene therapy, especially for cancer, is really starting to make a comeback."
The virus's selectivity for cancer cells is based on two molecules called PEA-3 and AP-1 that, the researchers found, are usually abundant inside cancer cells. Both of the molecules flip a switch (called PEG) that turns on the production of a cancer-inhibiting protein uniquely in tumor cells.
The researchers say the PEG switch can be exploited to produce gene therapies that will only kill cancer cells even if the therapy enters normal cells.
As an example, the researchers constructed an adenovirus that carries the PEG switch and a toxic protein. The switch and the protein were connected to each other so that the deadly protein is only unleashed inside cancer cells when the switch is flipped on by PEA-3 or AP-1.
When added to a mix of normal and prostrate cancer cells, the virus entered both but only produced the toxic protein inside the cancer cells. All the prostrate cancer cells died while the normal cells were unaffected.
The same virus also selectively killed human cancer cells from melanoma and ovarian, breast, and glioma (brain) tumors.
This approach is important because cancer can not be cured without the development of therapeutic agents that have far greater ability than current conventional chemical chemotherapy agents to selectively target cancer cells while leaving normal cells unharmed. The use of molecular switches that will flip on to deliver therapies only in cancer cells is going to be one of the major ways that cancer is going to be defeated and perhaps even ultimately the best way. There are two parts to such a therapy. The first is the switching part that detects unique signature patterns in cancer cells to know to activate. The other part is what will get done once the activation of the switch has happened. There are many possibilities for the second part. Imagine, for example, an enzyme that gets synthesized in cancer cells that can metabolize inert chemotherapy compounds into toxic forms. Or imagine a protein made from the switch that effectively punches a hole in a cell. Or perhaps the switch would turn on a bigger package of genes that would restore normal cell division regulation. The gene package could include a replacement non-mutated p53 cell divisiion regulating gene to replace the mutated p53 genes found in many types of cancer.
Update: After watching a lecture by Judah Folkman on anti-angiogenesis compounds to control cancer a thought occurs me: What would be neat would be a gene therapy that turns on anti-angiogenesis genes only in cells that are cancerous. Then anti-angiogenesis compounds would be produced in an area of the body only as long as cancer cells were growing in that area. Or imagine a gene therapy that only in cancer cells would make RNAi (RNA interference) segments against the messenger RNA for VEGF and other angiogenesis molecules.
There would be a distinct advantage, however, to a gene therapy that just killed all the cancer cells and even the pre-cancerous cells. A cell killing therapy would have the benefit of also being a rejuvenating therapy since it would wipe out a lot of damaged cells and therefore provide healthier cells room to grow. Depending on what internal conditions of a cell were used to activate the gene therapy it would be effective even in cancers that have not mutated to the point of being able to develop new vasculature. So evenl the very small (less than a millimeter) cancers (that most people die with undiagnosed) could be wiped out. Given that those damaged cancerous and precancerous cells are not doing their original jobs well (if at all) and are likely to be releasing inflaming molecules and/or free radicals one can expect a rejuvenating benefit from such a treatment.
I can easily imagine someone lying to their lover: "I have to take Viagra and act like this or my heart will fail. You don't want me to die, do you?"
Researchers at Johns Hopkins have found that sildenafil citrate (Viagra), a drug used to treat erectile dysfunction (ED) in millions of men, effectively treats enlarged hearts in mice, stopping further muscle growth from occurring and reversing existing growth, including the cellular and functional damage it created.
"A larger-than-normal heart is a serious medical condition, known as hypertrophy, and is a common feature of heart failure that can be fatal," says study senior author and cardiologist David Kass, M.D., a professor at The Johns Hopkins University School of Medicine and its Heart Institute. Kass is also the Abraham and Virginia Weiss Professor of Cardiology at Hopkins.
Sildenafil, Kass says, was the focus of his research because it blocks or stops an enzyme, called phosphodiesterase 5 (PDE5A), involved in the breakdown of a key molecule, cyclic GMP, which serves as a "natural brake" to stresses and overgrowth in the heart. "We thought we could more strongly apply the brake on hypertrophy in the heart if we used sildenafil to prevent the breakdown of cyclic GMP," he says. The makers of the drug had no involvement in the design or support of the research. PDE5A is also the biological pathway blocked in the penis to prevent the relaxation of blood vessels and maintain erections.
The Johns Hopkins findings, to be published in the journal Nature Medicine online Jan. 23, are the first to show that sildenafil is an effective treatment for a chronic heart condition. It is also the first study to reveal that the enzyme pathway blocked by sildenafil (PDE5A), never before known to play a significant role in the heart, is active when the heart is exposed to pressure stress and hypertrophied. The results provide some of the strongest evidence to date that blocking the heart's adaptive response to hypertrophy does not harm its function but, in fact, may improve it, Kass says. Already, plans are under way by the Hopkins researchers for a multicenter trial to test if sildenafil has the same effects on hypertrophy in humans.
In the first of several experiments, each involving groups of 10 to 40 male mice, the Hopkins team stimulated hypertrophy for up to nine weeks, but only by half as much in those that had also consumed sildenafil in their food at 100 milligrams per kilogram per day. In mice, this dose produces blood levels similar to those achieved in humans given standard clinical doses.
The mice fed sildenafil also showed 67 percent less muscle fibrosis, a complication that often occurs with hypertrophy, as compared to mice that were not fed the drug. The treated mice also had smaller hearts and improved heart function, whereas the untreated hearts were dilated with weakened function. For all mice with hypertrophy, the condition was surgically produced by constricting the main artery carrying blood from the heart to create pressure stress.
In a second experiment, the researchers used the same dose of sildenafil and examined its effects on reversing hypertrophy that had already occurred. Initially, these mice were exposed to pressure stress for seven to 10 days, with hearts developing fibrosis and muscle growth by nearly 65 percent. After two weeks of therapy, fibrosis and muscle growth almost completely disappeared. In mice that did not have therapy, hearts continued to get bigger.
In a surprising result, the researchers found that heart function, as measured by pressure-volume analysis of the muscle's ability to contract and pump blood, actually improved after hypertrophy had been stopped and treated. While researchers previously thought that hypertrophy was an adaptive response to pressure stress, the functional gains lasted despite the heart's continued exposure to high blood pressure. Improvements were seen in more than 10 measures of heart function, including heart relaxation, cardiac output and heart contractility, which increased by nearly 40 percent. These improvements were seen even when therapy was deferred and started two weeks after hypertrophy had already developed.
"This study shows that sildenafil can make hypertrophy go away," says Kass. "Its effects can be both stopped in their tracks and reversed. Overall, the results provide a better understanding of the biological pathways involved in hypertrophy and heart dilation, leading contributors to heart failure. They suggest possible therapies in the future, including sildenafil, which has the added benefit of already being studied as safe and effective for another medical condition."
This is a funny result. Picture millions of men in the future complaining they can't let it down because to do so would cause them heart failure. The future is going to be a strange place.
Capsules containing anti-cancer agents and coated with gold nanoparticles can be melted open in cancer cells using near-infrared lasers and someday this may be done in patients without damaging non-cancerous cells.
So Frank Caruso and his team at the University of Melbourne, Australia, are developing an ingenious way of doing this. Their trick is to enclose the drug in polymer capsules that are peppered with gold nanoparticles and attached to tumour-seeking antibodies.
When injected into the bloodstream, the capsules will concentrate inside tumours. When enough capsules have gathered there, a pulse from a near-infrared laser will melt the gold, which strongly absorbs near-infrared wavelengths. This will rupture the plastic capsules and release their contents.
This packaging is neat because it would prevent the damage that conventional chemotherapy causes to normal cells all over the body while en route to cancer cells.
What is the biggest problem with cancer treatment? Cancer cells are too like normal cells. Therefore it is hard to selectively kill cancer cells. It remains to be seen whether all cancer cells will have enough unique surface proteins to be targettable using antibodies. But for those cancer cells that do present distinct surface antigen patterns an approach like Caruso's to package and selectively deliver toxic compounds (or even gene therapies) to cancer cells is going to be what ends up curing many types of currently uncurable cancers.
Even if some types of cancer cells do not present a single unique antigen this approach could still be used to attack cancer cells. Suppose cancer cells present combinations of antigens that are rarely found in normal cells. A few interdependent chemo agents could be placed in different packages attached to different antibodies. Imagine cancer cells have antigens A, B, and C. Then chemicals X, Y, and Z could be packaged with antibodies aimed at antigens A, B, and C respectively. Then only cells that have all 3 of the targetted antigens on their surfaces that in combination mark them as cancer cells would get all the different types of chemical packages delivered to them. Think of this as analogous to explosives that work only when two or three different chemicals are mixed together. One could create chemical compounds that would act like metaphorical set of anti-cancer explosives. The chemicals would become deadly only when chemicals X, Y, and Z are all released from different packages into the same cell.
Monoclonal antibodies to deliver chemotherapy compounds are already in clinical trials. But Caruso's approach would allow most of the delivery packages to get into cancer cells and then to be released all at once to create a bigger spike in cancer cell killer compounds. Also, Caruso's approach would work better with compounds that would need to detach from their antibody delivery vehicles. Also, in Caruso's approach it seems likely that more chemo molecules could be delivered per antibody.
You can view a slide show and read text of a presentation that Caruso delivered in May 2003 that explains how some of the pieces of this capability were created. That presentation doesn't include the step of using antibodies to deliver capsules. But it does include some interesting bits of information on how the capsules were constructed to be able to be opened by a laser.
Update One problem with this approach is that it may not work well for cancers that have widely metastasized. I came across one report claiming that the near-infrared lasers can penetrate a few millimters of skin or be delivered endoscopically (and the light has to shine for only ten billionths of a second). But what if, for example, one has metastasized cancer to the bone? Lasers therefore seem problematic as activation agents. However, if capsules could be constructed to burst open in response to ultrasound then cancers in brains and other less accessible locations might be reachable with microcapsule chemo delivery vehicles.
Dr Jean-Marie Andrieu and Dr. Wei Lu have demonstrated that a vaccine prepared from a patient's own blood can keep HIV viral load down far enough to allow CD4 immune cell counts to rise.
French researchers reported Sunday that an AIDS vaccine designed to treat the disease, rather than prevent it, has scored an initial success by suppressing the virus for up to a year among a small group of patients who tried it.
The vaccine reduces viral load but does not wipe out the virus entirely.
The vaccine was tested in Brazil on 18 volunteers who were already infected with HIV, the virus that causes AIDS, but who were not yet taking any antiviral drugs. After four months, the level of HIV in their bloodstreams had been reduced an average of 80 percent.
The vaccine would cost $4000-$8000 per year and have to be taken yearly. That would be considerably cheaper than anti-retroviral drugs and would probably have far fewer side effects than the drugs.
Cells called monocytes were extracted from volunteers’ blood, grown in laboratory conditions and transformed into dendritic cells, which alert the immune system to possible infections. These dendritic cells were loaded with a chemically-inactivated preparation of HIV taken from the same person, and then transfused back into the trial volunteer.
In eight out of the 18, viral load fell by more than 90% (a one-log reduction) when measured one year after treatment, along with stable or rising CD4 counts. The other 10 also had reductions in viral load, but these were not sustained. Across the whole group, there was a statistically significant reduction of viral load over the course of the year and an increase in CD4 counts of around 100 cells/mm3 which returned over one year to baseline values. This contrasted with the six months before treatment, in which CD4 counts fell by an average of 100 cells.
While this obviously does not cure existing HIV carriers or prevent infections it will probably reduce treatment costs, reduce side effects (which can be debilitating and life-threatening), and reduce the burden and nuisance on patients of treating themselves.
Since wider spread use of a vaccine will reduce anti-viral drug use it will also reduce the rate at which drug-resistant HIV strains get selected for. So the anti-viral drugs will last longer for those who need them.
A vaccine that prevents new infections and a treatment that would totally wipe out HIV in a body would both greatly reduce treatment costs. Optimally effective medical treatments don't just make people healthier. They also almost always much cheaper than treatments that attempt to manage and control a medical condition without curing it entirely.
Scientists led by Walter Koch, Ph.D., director of the Center for Translational Medicine in the Department of Medicine in Jefferson Medical College of Thomas Jefferson University in Philadelphia, used a virus to insert the gene for a protein called S100A1 into failing rat hearts.
“In contrast to other gene therapy strategies geared to overexpressing a gene,” says Dr. Koch, who is W.W. Smith Professor of Medicine at Jefferson Medical College, “because this protein is reduced in heart failure, simply bringing the protein level back to normal restored heart function.” Dr. Koch and his co-workers report their findings December 1, 2004 in the Journal of Clinical Investigation.
S100A1, which is part of a larger family of proteins called S100, binds to calcium and is primarily found at high levels in muscle, particularly the heart. Previous studies by other researchers showed that the protein was reduced by as much as 50 percent in patients with heart failure. A few years ago, Dr. Koch and his co-workers put the human gene that makes S100A1 into a mouse, and found a resulting increase in contractile function of the heart cell. The mice hearts worked better and had stronger beats.
Dr. Koch’s Jefferson team now examined whether it could make failing hearts normal again. The researchers – 12 weeks after they simulated a heart attack in the rats – delivered the human S100A1 gene to the heart through the coronary arteries by injection of a genetically-modified common cold virus as a carrier. After about a week, they found the hearts began to work normally. In addition, the animals’ heart muscle showed improved efficiency in using its energy supply, which was decreased in heart failure. According to Dr. Koch, the improvements were seen in both the whole animal as well as in individual heart cells.
“This is one of the first studies to do intracoronary gene delivery in a post-infarcted failing heart,” he says. “This proves it could actually be a therapy since most of the previous studies of this type are aimed at prevention – giving a gene and showing that certain heart problems are prevented. In those cases, heart problems are not actually reversed. This is a remarkable rescue and reversal of cardiac dysfunction, with obvious clinical implications for future heart failure therapy.”
Koch hopes to eventually do human trials of this therapy.
Next, he and his colleagues hope to learn more about the mechanisms behind S100A1’s actions, and eventually, develop gene therapy protocols in humans. S100A1 is also found in the cell’s energy-producing mitochondria, he notes. He thinks the protein may be a link between energy production and calcium signaling in the heart cell – a crucial part of the process that makes the heart beat.
Between stem cell therapies and gene therapies I find it hard to believe that heart disease will be a major killer 20 years from now.
Here is a story of a significant advance for treating a chronic debilitating disease. While this latest treatment is a good thing that will benefit many sufferers of Multiple Sclerosis a comparison of the financial figures for drug costs, treatment costs, and other costs of MS versus the amount of money spent on MS research illustrates a larger problem in medicine today: too little money is spend on research into diseases that are costly to treat and costly to live with.
We start out first with the happy news. The US Food and Drug Administration has approved Tysabri for sale as a treament for MS.
Cambridge, MA; San Diego, CA; Dublin, Ireland – November 23, 2004 – Biogen Idec (NASDAQ: BIIB) and Elan Corporation, plc (NYSE: ELN) announced today that the U.S. Food and Drug Administration (FDA) has approved TYSABRI (natalizumab), formerly referred to as ANTEGREN®, as treatment for relapsing forms of multiple sclerosis (MS) to reduce the frequency of clinical relapses. FDA granted Accelerated Approval for TYSABRI following Priority Review based on one-year data from two Phase III studies, the AFFIRM monotherapy trial and the SENTINEL add-on trial with AVONEX®(Interferon beta-1a).
TYSABRI, the first humanized monoclonal antibody approved for the treatment of MS, inhibits adhesion molecules on the surface of immune cells. Research suggests TYSABRI works by preventing immune cells from migrating from the bloodstream into the brain where they can cause inflammation and potentially damage nerve fibers and their insulation.
Tysabri by itself greatly reduced the MS relapse rate.
AFFIRM is a two-year, randomized, multi-center, placebo-controlled, double-blind study of 942 patients conducted in 99 sites worldwide, in which patients were randomized to receive either a fixed 300 mg IV infusion dose of TYSABRI (n=627) or placebo (n=315) every four weeks. TYSABRI reduced the rate of clinical relapses by 66 percent relative to placebo (p<0.001), the primary endpoint at one-year. The annualized relapse rate was 0.25 for TYSABRI-treated patients versus 0.74 for placebo-treated patients.
AFFIRM also met all one-year secondary endpoints, including MRI measures. In the TYSABRI-treated group, 60 percent of patients developed no new or newly enlarging T2 hyperintense lesions compared to 22 percent of placebo-treated patients (p<0.001). On the one-year MRI scan, 96 percent of TYSABRI-treated patients had no gadolinium enhancing lesions compared to 68 percent of placebo-treated patients (p<0.001). The proportion of patients who remained relapse free was 76 percent in the TYSABRI-treated group compared to 53 percent in the placebo-treated group (p<0.001).
When combined with the existing Avonex drug (which is the protein hormone Interferon beta-1a) the result was a lower relapse rate than when used with Avonex alone.
Approval was also based on the results of another Phase III clinical trial, SENTINEL. SENTINEL is a two-year, randomized, multi-center, placebo-controlled, double-blind study of 1,171 AVONEX-treated patients in 123 clinical trial sites worldwide.
In the SENTINEL trial, AVONEX-treated patients who continued to experience disease activity were randomized to add TYSABRI (n=589) or placebo (n=582) to their standard regimen.
SENTINEL achieved its one-year primary endpoint. The addition of TYSABRI to AVONEX resulted in a 54 percent reduction in the rate of clinical relapses over the effect of AVONEX alone (p<0.001). The annualized relapse rate was 0.36 for patients receiving TYSABRI when added to AVONEX versus 0.78 with AVONEX plus placebo.
Note that the annualized relapse rate from the first trial that used only Tysabri was lower than the annualized relapse rate from the second trial of Tysabri and Avonex in combination. Though it is not clear that the sample sizes and the characteristics of the two sets of experimental subjects were comparable. Still, Tysabri looks like it is a more effective treatment of MS.
Some people can't handle existing anti-MS drugs due to the severity of side effects. Expect many of those patients to shift to Tysabri. Also, some may add Tysabri to existing treatments to reduce the odds of relapse.
Guesstimates have ranged from $20,000/year to as much as $30,000/year. By comparison, Avonex, Betaseron and Copaxone cost about $13,000 per year, Rebif $16,500 per year.
My guess is that Tysabri will put some downward pricing pressure on the other competiting drug treatments for MS. Also, its high price serves as an incentive for other pharmaceutical companies to develop better MS drugs. Estimates for Tysabri yearly peak sales range from $1 to $2 billion to $3 billion.. Estimates of the number of patients who can no longer use existing MS drugs in the US range from 40,000 to 50,000 all the way up to 175,000. Estimates for the number of MS sufferers in the US range from 350,000 to 400,000. Well, at a price of $30,000 year it would take 100,000 patients using Tysabri to reach $3 billion yearly sales. Currently the total market for MS sales split across all existing products is $4 billion. Total dollar volume of MS drug sales will likely grow as a result of Tysabri's introduction. In the longer run more MS drugs will be introduced to try to get a percentage of MS drug sales.
In the United States, the annual cost of MS is approximately $20 billion; this amount pales in comparison with the level of investment in MS research at NIH*. For FY'04 and FY'05, it is estimated NIH will spend $101.3 million and $102.8 million on MS research, respectively. Two NIH institutes primarily conduct or fund research on MS: NINDS that funds 75%, and NIAID that funds about 20%.
My guess (and this is a high confidence guess) is that the US government spends easily 20 or 30 times more money (through Medicare, Medicaid, and other government medical programs) to treat MS patients and to take care of MS patients than it does on research. This strikes me as very foolish. Auto-immune diseases (which MS is suspected of being along with rheumatoid arthritis and type I diabetes) will not be as hard to completely cure as, say, cancer or heart disease. There are many more research grant applicants than money to fund them. There is no shortage of qualified researchers who can be funded to speed up the rate of progress.
Let me put it another way: There are about 400,000 MS sufferers in the United States. The NIH is spending about $200 million per year on research. Well, that is about $500 in research per sufferer. Think about this in terms of lost tax revenue. Many MS sufferers can no longer work and therefore pay thousands of dollars less in taxes per year than they would if they were working. So MS is a net loss to the government even before getting to the cost of government-funded treatments. Throw on top of that the money that the US government pays to treat MS sufferers and the size of the effort to find a cure for MS seems penny wise but pound foolish. Of course the same argument probably holds for many other national governments as well. The Western nations ought to agree to large coordinated increases in research into a variety of diseases as a way to avoid huge future health care costs.
Consider the future pay-off. At some point in the future drugs that permanently halt MS will be introduced and the total dollar volume of MS drug treatments and other medical testing and treatments for MS will plummet. We are still on the uphill slope of MS drug sales though since all the existing treatments try to restrain the behavior of the immune system rather than retrain it to permanently deactivate or kill off immune cells that want to attack nerve cells. But once the knowledge becomes available to allow therapies to be developed that can fix the immune system MS treatment costs and all related medical care costs for MS sufferers (which are multiples of the few billion spent on these drugs) will plummet by orders of magnitude.
Update: Note that the introduction of this new MS drug is expected to cause MS drug sales to go up by $2 billion per year. That increase alone is about ten times more than the US government spends on MS research. The amount spent on research strikes me as far too low when we compare research expenditures with the amount of money spent on treatments that do not even work well. Look at this drug. Imagine you had MS. If the drug works on you like it does on the average patient it means you will get an MS relapse and deteriorate further about once every 4 years. Granted that is much better than what happens if you do not take the drug. But it is far from an optimal solution, either for your health, your ability to go on working and earning income comparable to what you make now, or in terms of costs.
The amount of money spent on medical research is incredibly small when compared to the amount spent on treatments. Worse yet, the gap between the amount spent on research and the amount spent on treatment is widening.
Under the compromise legislation, NIH will receive about $28.4 billion, a 2% increase of $563 million over last year. This will give most institutes and centers increases of 1.6% to 2.4%, failing to keep pace with the biomedical research and development price index, projected at 3.5%
Businesses will pay 7.8 percent more, on average, for employee health plans in 2005, even though many firms have shifted some premium costs to their workers, a new study projects.
Think about it: Medical spending costs are increasing while the total effort going into government funded medical research is decreasing. This seems like a huge mistake to me.
Health-benefits costs rose 7.5 percent this year, down from a 10.1 percent increase in 2003, according to a survey from Mercer Human Resource Consulting. Consumer-price inflation is running about 3 percent.
For 2005, employers forecast an overall cost increase of 6.6 percent, assuming they change plan designs, drop a plan or change vendors, the survey said. However, companies predicted a 10 percent increase if they were to stay with their current health plan and vendor.
Total medical costs are going up 10% while NIH funding is going up by 2%. Yet as I've previously argued: Scientific Advances Are The Solution To High Medical Costs.
Using ultrasound in combination with the drug t-PA can improve response to an ischemic stroke, according to a study involving 126 patients. This first-of-its-kind human trial compared the safety and efficacy of ultrasound and t-PA versus use of t-PA alone. The trial was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS), a component of the National Institutes of Health (NIH). The finding appears in the November 18, 2004, issue of the New England Journal of Medicine.
Since 1996, the clot-busting drug t-PA (tissue plasminogen activator) has been the only FDA-approved therapy for acute ischemic stroke. Previous studies have shown that t-PA, when administered within 3 hours of onset of ischemic stroke, can greatly improve a patient's chance for a full recovery. t-PA cannot be used to treat the less common hemorrhagic stroke.
Researchers wanted to test the effectiveness of using transcranial Doppler ultrasound (TCD) in combination with t-PA, and to ensure that ultrasound did not cause bleeding into the brain. Utrasound is a safe, non-invasive, FDA-approved diagnostic test that uses sound waves to measure blood flow velocity in large arteries. An international team led by Andrei Alexandrov, M.D., associate professor of neurology at the University of Texas-Houston School of Medicine, examined 126 patients who suffered an ischemic stroke. All patients received intravenous t-PA within 3 hours of stroke onset. The 63 patients in the control group received t-PA alone, while the other 63 patients received t-PA in combination with continuous TCD monitoring that started shortly before the patients received the drug. A small device attached to a head frame was used to deliver the ultrasound.
Results showed that 49 percent of patients who received continuous ultrasound and t-PA showed dramatic clinical improvement and little or no blockage within 2 hours after therapy began compared to 30 percent who received t-PA alone. Notably, 38 percent of the patients who received continuous ultrasound and t-PA showed no blockage within two hours, compared to 13 percent who received t-PA alone. In all, 73 percent of patients who received the combined therapy showed complete or partial clearance of the clot, compared to 50 percent in the control group. Bleeding into the brain was experienced by 4.8 percent of patients in both groups. This early improvement of blood flow to the brain resulted in a trend that 13.5 percent more patients who received continuous ultrasound and t-PA had recovered completely by 3 months after stroke.
The team also found that patients who experienced complete clearance of their clot within 2 hours following treatment had the greatest likelihood of regaining body strength, speech, and other functions affected by stroke. Researchers named the trial CLOTBUST (Combined Lysis Of Thrombus in Brain ischemia Using transcranial ultrasound and Systemic t-PA).
It will be cheap and easy to implement the lessons learned from this discovery and the benefits will be enormous.
This discovery was made by accident by an observant nurse. Emergency room nurse Patti Bratina observed that the stroke patients which were being monitored by Dr. Alexandrov using ultrasound recovered much better than typical stroke patients.
It happened at the University of Texas-Houston Medical School about five years ago, when Dr. Andrei V. Alexandrov, newly arrived from the University of Toronto, was using ultrasound technology to monitor the progress of stroke patients treated with tissue plasminogen inhibitor (tPA), a clot-dissolving drug that had just been given approval by the U. S. Food and Drug Administration for use against strokes (it had been approved for use in heart attacks more than a decade earlier). The nurse, Patti Bratina, noticed that many of the patients being monitored by Alexandrov were making remarkable recoveries, regaining use of their limbs and other faculties much faster than could be expected. Perhaps, she suggested, ultrasound had something to do with that.
Dr. Alexandrov wisely followed up on her suggestion. The result is a NEJM paper entitled Ultrasound-Enhanced Systemic Thrombolysis for Acute Ischemic Stroke.
Stroke is the third leading cause of death in the United States. It is the leading cause of long-term disability in the United States. Each year, more than 600,000 people suffer a stroke in the United States, resulting in approximately 150,000 deaths. The yearly cost of stroke in the United States is more than 40 billion dollars. Yet, one cannot fully measure the cost of stroke in dollars. The effects of stroke are felt not only by the patient, but also by the patient's family and friends, and by society in general.
There are about 4.4 million stroke survivors in the United States today and likely tens of millions more in the rest of the world. Imagine higher rates of recovery for the future millions of stroke sufferers. Costs in physical therapy, nursing services, and other costs will be reduced by a cheap and easy improvement in how stroke is initially treated in emergency wards.
Of course, the ideal solution to stroke will be therapies that prevent it from happening in the first place. My guess is we will need gene therapies or cell therapies to repair the cardiovascular system perhaps along with gene therapies to change blood chemistry in such a way that prevents cholesterol build-up. My guess is the liver would be the target for the latter category of gene therapies but the blood vessels would be the target of gene therapies designed to repair them.
Some types of spinal cord injury do not result in an immediate severing of the spinal cord and yet paralysis does eventually develop hours after the injury. A group of University of Rochester Medical Center researchers have pinpointed the reason for the neuronal cell death that produces paralysis: astrocyte support cells around a spinal injury respond to the injury by releasing ATP that signals to the neurons to kill themselves.
ATP, the vital energy source that keeps our body’s cells alive, runs amok at the site of a spinal cord injury, pouring into the area around the wound and killing the cells that normally allow us to move, scientists report in the cover story of the August issue of Nature Medicine.
The finding that ATP is a culprit in causing the devastating damage of spinal cord injury is unexpected. Doctors have known that initial trauma to the spinal cord is exacerbated by a cascade of molecular events over the first few hours that permanently worsen the paralysis for patients. But the finding that high levels of ATP kill healthy cells in nearby regions of the spinal cord that were otherwise uninjured is surprising and marks one of the first times that high levels of ATP have been identified as a cause of injury in the body.
The team found that excess ATP damages motor neurons, the cells that allow us to move and whose deaths in the spinal cord result in paralysis. Even more noteworthy was what happened when the research team from the University of Rochester Medical Center blocked ATP’s effects on neurons: Rats with damaged spinal cords recovered most of their function, walking and running and climbing nearly as well as healthy rats.
While the work opens up a promising new avenue of study, the work is years away from possible application in patients, cautions Maiken Nedergaard, M.D., Ph.D., the researcher who led the study. In addition, the research offers promise mainly to people who have just suffered a spinal cord injury, not for patients whose injury is more than a day old. Just as clot-busting agents can help patients who have had a stroke or heart attack who get to an emergency room within a few hours, so a compound that could stem the damage from ATP might help patients who have had a spinal cord injury and are treated immediately.
“There is no good acute treatment now for patients who have a spinal cord injury,” says Nedergaard. “We’re hoping that this work will lead to therapy that could decrease the extent of the secondary damage.
Anyone know how this team at Rochester blocked ATP's effects?
Neuronal support cells known as astrocytes release ATP that binds to the P2X7 receptor on neurons in such large concentraitions that the neurons interpret the binding as a signal to kill themselves in a cell suicide process known as apoptosis.
The findings come courtesy of the same technology that underlies the firefly’s mating habits. The firefly uses the enzyme luciferase to convert ATP to the glow it uses to light up and attract mates. Nedergaard’s team used the same enzyme to study the levels of ATP around the site of spinal cord injury, recording a very a bright signal for several hours around the site of injury.
While low levels of ATP normally provide a quick and primitive way for cells to communicate, Nedergaard says, levels found in the spinal cord were hundreds of times higher than normal. The glut of ATP over-stimulates neurons and causes them to die from metabolic stress.
Neurons in the spinal cord are so susceptible to ATP because of a molecule known as “the death receptor.” Scientists know that the receptor, also called P2X7, also plays a role in regulating the deaths of immune cells such as macrophages, but its appearance in the spinal cord was a surprise. ATP uses the receptor to latch onto neurons and send them the flood of signals that cause their deaths. Nedergaard’s team discovered that P2X7 is carried in abundance by neurons in the spinal cord.
The source of the ATP that kills the neurons provided another revelation for researchers. Star-shaped cells known as astrocytes, long considered simply as passive support cells for neurons in the nervous system, produce the high levels of ATP.
This discovery opens up several avenues of attack for the development of treatments. First of all, a method might be found to create a chemical environment around the astrocytes that looks like no injury has occurred. The astrocytes would not react to the injury because the chemical changes caused by the trauma effectively would be hidden from them. Another possibility would be a drug that would bind somewhere in astrocytes to suppress ATP release even though the astrocytes are getting external signals typical of trauma. At the intermediate point between ATP release and ATP binding methods of getting rid of the ATP might be employed. For instance, a drug that would catalyze the breakdown of ATP would eliminate the ATP after it was released by the astrocytes. Another possibility would be a drug that would compete with ATP to bind at the P2X7 site. Such a drug would need to be able to bind at the site while not triggering the receptor to change shape the way ATP does when ATP binds at the site. A fourth target area would be within the neurons. A cascade of events within neurons is set off by ATP binding to P2X7. It might be possible to find drugs that will interrupt that cascade at any number of stages to prevent cell death.
Discoveries that point in a clear direction for where to intervene in a disease process do not get as much attention as do actual treatments. Yet the identification of high quality targets for intervention greatly speed up the development of treatments. This discovery of the importance of ATP and the P2X7 receptor is probably going to lead to the development of a number of treatments that will prevent paralysis after many spinal cord injuries and other types of nerve injuries.
Researchers at Northwestern University have developed a technique that delivers into rat brains genes that can be switched off with the use of an antibiotic.
Northwestern University neuroscientists have overcome a major obstacle in gene therapy research. They've devised a method that will safely deliver and regulate expression of therapeutic genes introduced into the central nervous system to treat Parkinson's disease and other neurodegenerative diseases.
The method, developed by Martha C. Bohn and colleagues, is described in the June issue of the journal Gene Therapy. Bohn is Medical Research Institute Council Professor of Pediatrics at the Children's Memorial Institute for Education and Research and professor of pediatrics and of molecular pharmacology and biological chemistry at Northwestern University Feinberg School of Medicine.
Jiang Lixin, a post-doctoral fellow in Bohn's laboratory, created three different viral vectors -- carrier molecules -- that used human fluorescent green protein to track gene delivery and expression in cells. The vectors, made with the harmless adeno-associated virus (AAV), carried the "tet-off" system, in which the introduced gene is continually expressed or "on" but can be temporarily "turned off" when a small dose of the tetracycline antibiotic derivative doxycycline is administered.
One vector, known as rAAVS3, displayed particularly tighter regulation in neurons when gene expression was measured at the protein and molecular RNA levels.
To assess regulation in the brain, the researchers injected the vector into the striatum of rats, the area in the brain where the neurotransmitter dopamine activates the nerve cells that control motor coordination.
In their experiments, Bohn and co-researchers found that up to 99 percent of the vector-introduced gene was turned off when the rats were given small doses of doxycycline. In Parkinson's disease, dopamine-producing neurons degenerate, resulting in gait problems, muscle rigidity and tremors
Several years ago Bohn's laboratory group discovered that glial cells in the embryonic brain stem secrete factors, or proteins, that promote survival and differentiation of dopamine neurons.
One of these proteins, called glial cell line-derived neurotrophic factor (GDNF), is a potent factor that promotes growth of not only dopamine neurons, but also motor neurons and several other types of neurons. GDNF may have therapeutic potential for several neurodegenerative diseases, including Parkinson's disease and Lou Gehrig's disease.
Bohn's laboratory was the first to show that introduction of a GDNF gene in a rodent model of Parkinson's disease halts the disease process.
"GDNF gene therapy has exciting potential to 'cure' Parkinson's disease, but since putting a gene into the brain may lead to expression and increased levels of GDNF protein for years, it will be important to have some way to turn off gene expression to arrest unanticipated side effects," Bohn said.
Bohn and her colleagues have been developing viral vectors that offer a safe means to deliver GDNF, as well as other therapeutic genes. The AAV vector that the researchers used in these experiments is safe and approved for use in several clinical trials in the brain of humans; however, no vector in which the gene can be turned off is yet approved for use in clinical trials.
"A crucial piece of our research is related to safety," Bohn said. "We were excited to find the right mechanism to deliver the gene into the nervous system and tightly control its expression using doxycycline, a drug already approved by the Food and Drug Administration and found to have no side effects."
Bohn cautioned that thorough safety and toxicity studies of the new vector are needed and that her laboratory group is not ready to assess its use in humans.
The mechanism these researchers are using delivers a gene that expresses unless the doxycycline is delivered. But for some therapeutic applications what will be needed is the ability to deliver a gene that will by default not express. Then delivery of a drug would be used to turn it on for some finite period of time. In some ceases one can imagine why it would be helpful to turn on a gene periodically. We really need a large variety of types of gene switches where a gene delivered by gene therapy can be flipped on to stay on or flipped off to stay off or stay on temporarily to stay off temporarily. Plus, we need better ways to deliver genes only into specific desired target cell types.
One might think that the bigger challenge of gene therapy is developing the gene or genes to deliver. But so far the biggest challenge has been in various aspects of delivery. We need better ways to get genes into cells, in only into specific cell types, in amounts no higher or lower than desired, and in ways that do not cause damage to the normal DNA in each cell. It is hard to guess at the rate gene therapy will advance because really good delivery mechanisms have turned out to be very difficult to develop.
Once genes with control switches can be easily and reliably delivered into brain neurons consider the James Bond angle: brains could be surreptitiously programmed to alter their behavior in response to some environmental exposure. Imagine some scent that carries a chemical that has a switch in it that turns genes in the brain on or off. A guy goes into a room, smells the perfume that Sydney Bristow of Alias is innocently (or not so innocently) wearing and suddenly he goes berzerk and starts trying to kill someone that the Covenant knows he hates.
There is also the large group control aspect. A country that need killer soldiers may need the soldiers to be mild mannered civilians between wars but homicidal killers when sent on missions. Well, flip a few switches and suddenly the special forces are chafing at the bit to inflict suffering and death. Or an entire society could be rendered docile during a coup attempt by putting something into the water supply to flip genetic switches that were gradually installed via insect-born vectors in all the brains in a capital city without being noticed.
Ehud Shapiro and his team at the Weizmann Institute of Science in Israel have published a paper in Nature on a DNA computer that activates in the presence of genes that indicate a cell is cancerous.
Scientists have built a tiny biological computer that might be able to diagnose and treat certain types of cancer. The device, which only works in a test-tube, is years from clinical application. But researchers hope it will be the precursor of future 'smart drugs' that roam the body, fixing disease on the spot.
Prof Shapiro's device is a development of a biological computer that he first built in 2001. DNA is the software of life: it carries huge quantities of information, programs the operating system of every cell, controls the growth of the whole organism and even supervises the making of the next generation.
In one example, the computer determined that two particular genes were active and two others inactive, and therefore made the diagnosis of prostate cancer. A piece of DNA, designed to act as a drug by interfering with the action of a different gene, was then automatically released from the end of the computer.
This ability to use multiple inputs is needed to accurately detect cancers since any one gene can be on or off at different times in normal cells. We need the ability to check many indicators in each cell to decide whether it is a cancer cell. Still more precise activation mechanisms could be constructed using more gene expression levels as inputs and by making yet more complex sensor mechanisms that detect length of activation of genes or ratios of expression of genes.
The software molecules follow a simple computational path. If they attach to normal mRNA, they do nothing; if they attach to abnormal mRNA, indicating the presence of a disease cell, they initiate a process to unleash a DNA treatment molecule modelled on an anticancer drug.
The Weizmann Institute press release provides more details on the DNA computer state machine and its ability to measure concentrations of molecules as inputs to make a decison on whether to activate its treatment.
As in previous biological computers produced in Shapiro’s lab, input, output and “software” are all composed of DNA, the material of genes, while DNA-manipulating enzymes are used as “hardware.” The newest version’s input apparatus is designed to assess concentrations of specific RNA molecules, which may be overproduced or under produced, depending on the type of cancer. Using pre-programmed medical knowledge, the computer then makes its diagnosis based on the detected RNA levels. In response to a cancer diagnosis, the output unit of the computer can initiate the controlled release of a single-stranded DNA molecule that is known to interfere with the cancer cell’s activities, causing it to self-destruct.
In one series of test-tube experiments, the team programmed the computer to identify RNA molecules that indicate the presence of prostate cancer and, following a correct diagnosis, to release the short DNA strands designed to kill cancer cells. Similarly, they were able to identify, in the test tube, the signs of one form of lung cancer. One day in the future, they hope to create a “doctor in a cell”, which will be able to operate inside a living body, spot disease and apply the necessary treatment before external symptoms even appear.
The original version of the biomolecular computer (also created in a test tube) capable of performing simple mathematical calculations, was introduced by Shapiro and colleagues in 2001. An improved system, which uses its input DNA molecule as its sole source of energy, was reported in 2003 and was listed in the 2004 Guinness Book of World Records as the smallest biological computing device.
Shapiro: “It is clear that the road to realizing our vision is a long one; it may take decades before such a system operating inside the human body becomes reality. Nevertheless, only two years ago we predicted that it would take another 10 years to reach the point we have reached today.”
I love this approach. Why? Because the use of a treatment that operates as a state machine attempts to solve the problem of cancer on the level that the mechanisms of cancer operate. Cells are really complex state machines. Our genome is a really complex computer program executing with biochemical mechanisms. Cancers result when that state machine becomes damaged in enough places to lose control of the process of cell division. What we need is a smaller state machine to go into cells, recognize which cells have damage to their programs that make them cancerous, and then to either order those cells to die or to fix the damaged pieces of the cellular program that make those cells cancerous in the first place.
Genetic instructions are the right way to develop a complex state machine to use as a cancer treatment. DNA can have far more complex behavior than any conventional drug compound. The DNA can interact with the messenger RNA made by the cells to ascertain a cell's state and to change that state. Genes and other DNA fragments contain far more information than os contained in conventional chemical drug structures. Groups of genes can function as rather complex state machines. Since cancer cells and normal cells have so much in common a high level of sophistication of behavior is needed in order to develop enough selectivity to identify and manipulate cancer cells.
What these Israeli scientists are doing is the future of medicine. There are still many hurdles in the way of making a DNA state machine drug treatment work. Most notably, a lot of scientists have been trying for years to develop gene therapy delivery mechanisms for getting gene therapies into cells and the advances have been slow in coming. A gene therapy approach that delivers a DNA state machine computer would need to be able to get into nearly all the cancer cells in the body. If effetive gene therapy delivery mechanisms can be developed then DNA computer hackers can start hacking the human body to fix what is broken and improve us in numerous ways.
A number of afflictions of humans in the modern era are a result of the fact that natural selection adapted us to environments so different than the environments of modern industrial societies. Obesity was not much of a problem in the past because for most of human history there was rarely much surplus food. The same is the case with salt cravings where, again, in the past there was usually not enough sodium in the foods our ancestors had to eat. Similarly, drug and alcohol addiction are obviously the result of the lack of human adaptiveness to substances they rarely encountered in the past. However, alcoholism susceptibility is less frequent among Mediterranean populations that have been growing grapes and making wine for centuries. So there are human populations that have developed at least partial genetic adaptations to ethanol consumption.
Some scientists have been advancing theories to explain some auto-immune disorders as being the result of lack of exposure to diseases that used to be common in the human past. Among the diseases suspected as being a consequence of lack of exposure to diseases are the painful digestive tract disorders inflammatory bowel disorder (IBD) and Crohn's Disease. Joel Weinstock MD, a professor of internal medicine at University of Iowa, and colleagues have demonstrated that eggs of pig whipworm, when consumed by suffers of Crohn's Disease (CD) and Ulcerative Colitis (UC), greatly reduce symptoms of those diseases.
). To assess safety and efficacy with repetitive doses, two patients with CD and two with UC were given 2500 ova at 3-wk intervals as maintenance treatment using the same evaluation parameters. RESULTS: During the treatment and observation period, all patients improved clinically without any adverse clinical events or laboratory abnormalities. Three of the four patients with CD entered remission according to the Crohn's Disease Activity Index; the fourth patient experienced a clinical response (reduction of 151) but did not achieve remission. Patients with UC experienced a reduction of the Clinical Colitis Activity Index to 57% of baseline. According to the IBD Quality of Life Index, six of seven patients (86%) achieved remission. The benefit derived from the initial dose was temporary. In the maintenance period, multiple doses again caused no adverse effects and sustained clinical improvement in all patients treated every 3 wk for >28 wk. CONCLUSIONS: This open trial demonstrates that it is safe to administer eggs from the porcine whipworm, Trichuris suis, to patients with CD and UC. It also demonstrates improvement in the common clinical indices used to describe disease activity. The benefit was temporary in some patients with a single dose, but it could be prolonged with maintenance therapy every 3 wk. The study suggests that it is possible to downregulate aberrant intestinal inflammation in humans with helminths.
At the moment the concoction cannot be stored for long, so doctors or hospitals would have to prepare fresh batches of the eggs for their patients. But a new German company called BioCure, whose sister company BioMonde sells leeches and maggots for treating wounds, hopes it will soon solve the storage problem.
If you find this idea completely revolting and perversely want to be even more revolted then see a picture of these worms or see this other picture of the worms so you can intensify your feelings of being grossed out by the idea of eating digestive tract worm eggs. Yes, picture worms wriggling around in your guts and say "Oh that is so gross! That is so disgusting!"
Okay, are you done imagining swallowing slimy worms that wriggle around in your mouth? Back to the science.
A pair of researchers at Scripps Research Institute, Nora Sarvetnick and Cecile King, are proposing a mechanism by which a lack of expsoure to pathogens causes autoimmune responses that cause diseases such as type I diabetes and rheumatoid arthritis.
According to the new hypothesis that Nora Sarvetnick and her colleague Cecile King are proposing, the root cause of autoimmunity is a failure to make an adequate response to an infection—in other words, an immune system that is not working hard enough (one that is hyporesponsive). This hyporesponsiveness creates a condition known as lymphopenia, where there is a reduction in the number of T cells in the body. Often people with autoimmune diseases like Type 1 diabetes, lupus, and rheumatoid arthritis have low T cell numbers.
If the body detects low levels of T cells, it resorts to homeostatic expansion, a mechanism that has never been associated with autoimmunity before. Under homeostatic expansion, growth signals stimulate the existing T cells in the body to divide and multiply.
This homeostatic process should normally fill the body, but sometimes that does not happen due to disrupted growth signals or a viral infection that causes the number of T cells to go down even as the body is trying to increase their numbers. These are the conditions that lead to autoimmunity, says Sarvetnick.
Sarvetnick, King, and colleagues Alex Ilic and Kersten Koelsch have shown that in a mouse strain genetically engineered to develop type I diabetes that they can prevent the development of the diabetes by feeding them bacterial cell wall components that keep up their T cell counts.
In their paper, Sarvetnick and her colleagues showed that NOD mice can be protected against diabetes by challenging them with a swill of bacterial cell wall components called CFA, which increased the T cell count and curtailed the development of diabetes in the mice.
To show that this effect was due to the increase in T cell count following the CFA administration and not some other cause, they passively stimulated the immune systems of NOD mice by infusing them with T cells. These infusions also prevented the NOD mice from developing diabetes.
According to Sarvetnick's and King's hypothesis, the protection against diabetes results from exposure to these pathogens because it keeps the body full of immune cells. Increased numbers of T cells act as a buffer against the emergence of self-reactive T cells by shutting down homeostatic expansion.
This hypothesis could explain a discrepancy in the number of cases of autoimmune disease in developed and developing countries. Disease rates have been on the rise in developed countries in the last 50 years compared to their developing neighbors, presumably because people in less developed countries are exposed to more pathogens.
Now, some of you may rather eat worm eggs or even wriggling worm eggs to treat your autoimmune disorders. But I think Sarvetnick, King, and company are performing a useful public service by searching for a treatment based on bacterial cell wall components.
In the longer run expect to see the development of vaccines that stimulate the immune system in ways that greatly decrease the odds of development of autoimmune disorders. Some of these future vaccines may even cure existing autoimmune disorders.
When an accident or any other event damages nerve cells much of the nerve cell death and resulting disability occurs hours or even days after the traumatic event. The injured nerves, many of which are not damaged in ways that make death inevitable, go through changes that cause them to commit cell suicide. Two approaches for how to prevent nerve cell death have just been reported. The first approach, tried at Wake Forest University, involves use of so-called heat stress proteins which normally are found inside of cells but which if delivered outside of cells still prevent a substantial fraction of damaged nerve cells from dying.
WINSTON-SALEM, N.C. – New findings in animals suggest a potential treatment to minimize disability after spinal cord and other nervous system injuries, say neuroscientists from Wake Forest University Baptist Medical Center.
“Our approach is based on a natural mechanism cells have for protecting themselves, called the stress protein response,” said Michael Tytell, Ph.D., a neuroscientist and the study’s lead researcher. “We believe it has potential for preventing some of the disability that occurs as a result of nervous system trauma and disease.”
The research showed that up to 50 percent of the motor and sensory nerve cell death could be prevented in mice with sciatic nerve injury. It is reported in the current issue of Cell Stress and Chaperones, a journal of stress biology and medicine.
“We are on our way to developing a treatment that is effective in preventing motor nerve cell death, which is significant to people because loss of motor neurons means paralysis,” said Tytell, professor of neurobiology and anatomy at Wake Forest Baptist.
The goal of the work is to prevent or minimize the “secondary” cell death that occurs in the hours and days after a spinal cord or brain injury. During this period, cells surrounding the injury can become inflamed and die, a cascading response that worsens disability.
Either these proteins could be delivered at injury sites or drugs could be developed to stimulate the production of Hsc70 and Hsp70 in damaged nerve cells.
For the study, the researchers treated injured sciatic nerves in mice with Hsc70 and Hsp70. In mice treated with the proteins, cell death was reduced by up to 50 percent compared to mice that weren’t treated.
Tytell said it is a novel idea that cells can be successfully treated with a protein that is ordinarily made inside the cells.
“We don’t know whether the protein is functioning in the same way as when it’s made in the cells,” he said. “We’re working to learn more about this effect. If we can understand it better, we’ll know what form it should be in and what the doses should be to maximize the protective benefits.”
Tytell and colleagues hope to use their knowledge about the proteins and how they work to develop drugs that could be used to treat injury. One idea is to develop a drug that would increase the production of the protective proteins.
Another group which includes lead author Sung Ok Yoon of Ohio State University used an antibody to neutralize a protein released by damaged nerve cells that plays a role in causing cell death.
Researchers report in the current online issue of the Proceedings of the National Academy of Sciences that they were able to prevent the death of damaged neurons by neutralizing a specific protein the injured cells secreted. Neurons carry messages from the brain to the spinal cord and the rest of the body.
Damaged neurons are rendered useless by the physical interaction of two cellular proteins – proNGF and p75, the researchers report. They learned that treating these injured cells with a proNGF antibody kept the proteins from interacting. In turn the neurons were saved from almost certain loss.
The approach of using an antibody to neutralize proNGF (which is a precursor to Nerve Growth Factor) saved most of the cells that otherwise would have died.
The researchers saw substantial increases in proNGF and p75 in damaged neurons within 24 hours after injury. Levels of p75 peaked three days after injury, as did neuronal death.
The researchers took another group of damaged neurons and treated these cells with an antibody to proNGF. Doing so kept proNGF from interacting with p75, and resulted in a 92 percent survival rate of otherwise damaged neurons.
"The antibody notably reduced the number of neurons that normally die after such injury," Yoon said. "But it's too soon to say if these rescued cells would function normally again after treatment."We do know that injury decreased the number of healthy, viable neurons by half," she said. "But the number of intact neurons remained at nearly 100 percent after antibody treatment."
To treat cancer what we need are better ways to cause cell death and to prevent cells from dividing. To develop stem cell therapies we need better ways to order cells to move to desired target locations, to divide, and to become specialized for various purposes. But for nerve cell damage caused by trauma or perhaps by toxins what we need is the ability to prevent the series of steps that lead cells to commit suicide (caled apoptosis). That two different teams have almost simultaneously come up with two different approaches for doing this in lab settings is encouraging. These results are not going to immediately lead to new treatments but they do demonstrate that such treatments are probably possible to create and these results provide useful information about what directions to pursue for further research.
Cancer is a particularly difficult disease to treat because cancer cells are host cells. It is hard to develop methods to selectively kill some host cells while not killing too many of the normal cells. Reports of interesting approaches for doing so are always interesting. The first here is the use of stem cells to go to where the cancer is located to deliver a treatment payload.
SAN DIEGO -- Genetically engineered stem cells can find tumors and then produce biological killing agents right at the cancer site, say researchers at The University of Texas M. D. Anderson Cancer Center, who have performed a number of successful "proof of concept" experiments in mice.
Their novel treatment, presented at the annual meeting of the American Society of Hematology (ASH), may offer the first gene therapy "delivery system" capable of homing in on and then attacking cancer that has metastasized -- wherever it is in a patient's body. And the stem cells will not be rejected, even if they are not derived from the patient.
The researchers have tested the system in mice with a variety of human cancers, including solid ones such as ovarian, brain, breast cancer, melanoma and even such blood-based cancer as leukemia. "This drug delivery system is attracted to cancer cells no matter what form they are in or where they are," says Michael Andreeff, M.D., Ph.D., professor in the Departments of Blood and Marrow Transplantation and Leukemia. "We believe this to be a major find."
M. D. Anderson has filed patent applications on the system, which uses human mesenchymal progenitor cells (MSC), the body's natural tissue regenerators. These unspecialized cells can migrate to an injury by responding to signals from the area. There they develop the kind of connective tissue that is needed to repair the wound, and can become any kind of tissue required.
Tumors are "never-healing wounds" which use mesenchymal stem cells to help build up the normal tissue that is needed to support the cancer, says Andreeff. "There is constant remodeling of tissue in tumors," he says. So researchers turned the tables on the cancer, taking advantage of a tumor's ability to attract the stem cells.
In their novel delivery system, researchers isolate a small quantity of MSC from bone marrow, and greatly expand the quantity of those cells in the lab. They then use a virus to deliver a particular gene into the stem cells. When turned on, this gene will produce an anti-cancer effect. When given back to the patient through an intraveneous injection, the millions of engineered mesenchymal progenitor cells will engraft where the tumor environment is signaling them, and will activate the therapeutic gene.
In the study reported at ASH, the researchers examined whether MSC producing human interferon-beta can inhibit the growth of metastatic tumors in the lungs of mice that do not have a functioning immune system. They used an adenovirus vector to deliver the gene that expresses interferon-beta, which can prevent cell reproduction. Andreeff and his team found that when mice were treated with just four weekly injections, their lifespan doubled, on average. They also discovered that when treated cells were placed under the skin of the mice, there was no effect. "The cells need to be in the immediate environment of the tumor to work," which suggests that normal tissue will not be adversely affected, says Andreeff.
Other studies being reported by Andreeff that used different therapeutic "payloads" found a doubling of survival in mice with one kind of ovarian cancer and a cure rate of 70 percent in mice with a different kind of ovarian tumor. Another study demonstrated that when the gene therapy was injected into the carotid (neck) artery of mice with human brain cancer, the genes incorporated themselves into the cancer, not into normal brain tissue.
This is a very cool result. One question is whether the stem cells will stick around to cause problems by expressing their payload genes. But if the stem cells come from another host then the body's own immune system will probably eventually wipe out the foreign stem cells after they have done their job.
Another treatment approach utilizes the fact that many cells in a tumor tend not to be well fed. A rapidly growing tumor usually has areas where some cells are not near capillaries and that are therefore oxygen starved. Those cells actually have a survival advantage against many chemotherapeutic agents because either agents can't be given in high enough dosages to seep into those cells or the chemo works better on active cells by reacting to oxygen in order to activate or for some other reason related to metabolism of active cells. KuDOS Pharmaceuticals and Novacea are working with a compound that is activated by a metabolic pathway that is typically only active in cells that lack oxygen.
South San Francisco, Calif. and CAMBRIDGE, United Kingdom, Dec. 11, 2003 -- Novacea Inc. and KuDOS Pharmaceuticals announced today that Novacea has licensed from KuDOS the North American rights to develop and commercialize AQ4N, a novel proprietary hypoxic cell-activated agent with broad potential in a variety of cancers.
As a first-in-class hypoxic cell-activated anti-tumor therapy, AQ4N represents a new approach to cancer treatment. The drug is considered inactive when administered and is selectively converted into its active cytotoxic form, known as AQ4, once it reaches hypoxic tumor cells (cells that are oxygen starved), reducing potential systemic toxicity. AQ4 is a potent topoisomerase II inhibitor and DNA intercalator.
More than two million patients each year are estimated to present with tumors in the U.S. and Europe. The large majority of these tumors have hypoxic components, which are relatively resistant to standard anti-cancer treatment, including radiotherapy and chemotherapy. As a result, a specific agent like AQ4N that can treat the hypoxic fractions should enhance the overall efficiency of cancer cell killing and reduce tumor recurrence.
Preclinical data demonstrate that AQ4N markedly enhances the effects of radiation and chemotherapy when administered in combination with either treatment. Data further suggest anti-tumor activity as a monotherapy. The agent is currently being evaluated in a Phase 1 clinical trial in combination with radiation in esophageal cancer. Sixteen patients have been treated to date and AQ4N has been well tolerated, with no serious drug-related adverse events reported.
AQ4N was originally discovered by Prof. Lawrence Patterson of the School of Pharmacy, at University of London, working in collaboration with BTG International plc (BTG). KuDOS acquired a worldwide license for AQ4N from BTG in March 2001.
While AQ4N is at best only going to kill a subset of cancer cells that targetted subset too often escapes death from current chemotherapeutic agents. So in combination with existing chemotherapeutic agents it might turn out to be a useful treatment.
Update: Another unusual anti-cancer therapy under development by Dr. William Wold of the Saint Louis University School of Medicine and his colleagues genetically engineers adenoviruses that cause common colds to instead selectively kill cancer cells.
Dr. Wold, chair of the department of molecular microbiology and immunology, and his colleagues Karoly Toth, Konstantin Doronin, Ann E. Tollefson, and Mohan Kuppuswamy have found a way to convert the relatively benign "adenovirus" that causes the common cold into an anti-cancer drug that attacks and destroys cancerous cells.
"Human cancer is currently treated with surgery, radiation therapy, or chemotherapy, depending on the cancer type," Wold said. "These treatments can be highly successful, but new therapies are required, especially for tumors that have become resistant to chemo- or radiation-therapy."
Wold's group has developed several new "adenovirus cancer gene therapy vectors," changing these genes so the virus will attack cancer cells.
"Some of our vectors are designed to destroy many different types of cancers, others are designed to be specific to colon or lung cancer. In preclinical testing these vectors were highly effective against cancerous tumors and did not harm normal tissues."
Wold and his colleagues have done this by modifying one gene so that the virus can grow in cancer cells but NOT normal cells and by boosting the activity of another gene that the virus normally uses to disrupt the cells it has infected. "When the virus infects cells, it takes the altered genes with it, and those genes attack cancer cells while leaving normal cells intact," Wold explained.
A U.S. patent (No. 6,627,190) was awarded this fall to Dr. Wold and his team of researchers. Pre-clinical testing is complete and is expected to move soon into clinical trials.
Now this patented technology has been issued and exclusively licensed to a company, Introgen Therapeutics, which made the announcement this morning. Introgen and VirRx, a biotechnology company founded by Wold and with a primary interest in cancer gene therapy, are collaborating on new therapies for cancer and other diseases.
AUSTIN, Texas, Dec. 16 /PRNewswire-FirstCall/ -- A patent that covers an important class of replicating adenoviruses relating to Introgen Therapeutics' anti-cancer product candidate INGN 007 (VRX 007) has been issued and exclusively sub-licensed to Introgen, the company announced today. The United States patent, U.S. 6,627,190, emanates from research performed at VirRx, Inc. and Saint Louis University under the direction of Dr. William S.M. Wold, one of the world's leaders in replicating oncolytic virus technology. Introgen and VirRx are collaborating on new therapies for cancer and other diseases. VirRx, LLC was founded by Dr. Wold.
INGN 007 is an oncolytic virus product that over-expresses the ADP gene, the protein responsible for the rapid disruption (oncolysis) of tumor cells and, hence, is an important therapeutic activity of oncolytic viruses. Oncolytic viruses are viruses that kill cancer cells by replicating at high levels and cause a cancer cell to break apart. In animal models, INGN 007 has demonstrated that it saturates the entire tumor treated and has shown it can eradicate cancer. Introgen and VirRx initiated their collaboration in order to develop a series of potential products emanating from VirRx and the Wold laboratory. Preclinical testing of INGN 007 is now being completed and the product is being readied for clinical development.
It isn't clear why this cell death effect is specific to cancer cells. A couple of Journal of Virology abstracts of Wold and his colleagues here and here refer to Transforming growth factor β1 (TGF-β1) but are they trying to turn it off or on in cancer cells and why is the mechanism not also going to kill normal cells? Again, it is not clear. Anyone have any insights on this?
Intravenous doses of a synthetic component of "good" cholesterol reduced artery disease in just six weeks in a small study with startlingly big implications for treating the nation's No. 1 killer.
How would you like to quickly reduce your risk of heart attacks or the pain from angina?
In a small, preliminary study, the laboratory-made substance, which mimics a type of cholesterol discovered in a group of surprisingly healthy villagers in rural Italy, significantly reduced in just six weeks the amount of plaque narrowing arteries of heart attack and chest pain patients, the researchers reported.
Note to life extension skeptics: With this report is there any reason to think artery hardening will be a major cause of mortality in industrialized countries 20 years from now?
The development of this investigational drug is an unusual story. About 30 years ago, researchers discovered 40 individuals in Limone Sul Garda in Northern Italy who appeared perfectly healthy, despite having very low levels of good cholesterol. Ordinarily, such people would have a high risk of heart disease, but these people did not. Intrigued, researchers wanted to find out why. Their studies revealed a variant in a protein known as Apolipoprotein A- I, which is a component of HDL. This variant was named ApoA-I Milano after the city of Milan, where the initial laboratory work was done.
ApoA-I Milano is being developed into a potential treatment for heart disease by Esperion Therapeutics Inc., an Ann Arbor, Mich.-based biopharmaceutical company. Esperion's investigational treatment, designated ETC-216, is a recombinant version of ApoA-I Milano combined with a phospholipid. After pre-clinical studies showed rapid removal of plaques from diseased arteries, scientists at Esperion came to Dr. Nissen to help them design a study to determine whether infusions of the ApoA-I Milano/phospholipid complex could reverse coronary plaque buildup in patients with heart disease.
The Cleveland Clinic-directed study administered the ApoA-I Milano/phospholipid complex intravenously over a five-week period to a randomized group of patients initially hospitalized for acute chest pain. Researchers measured arterial plaques using intravascular ultrasound (IVUS) before and after the six-week study. Patients who were given the synthetic protein showed a dramatic decrease in arterial plaques, whereas a comparison group given saline showed no change in plaques.
"These results demonstrate for the first time that it is possible to rapidly regress the major underlying cause of heart attack," said Roger S. Newton, Ph.D., President and CEO of Esperion Therapeutics. "By enhancing the removal of cholesterol from plaques in artery walls, a process known as reverse lipid transport, HDL therapy may provide an innovative approach to the treatment of atherosclerosis. We are excited about these results and look forward to continuing the development of ETC-216 in more patients with longer follow-up and assessing more endpoints, including morbidity and mortality."
In the Phase 2 clinical trial, 47 patients with acute coronary syndromes (ACS) received five weekly intravenous infusions of placebo (n=11 patients), ETC-216 at 15 mg/kg (n=21 patients) and ETC-216 at 45 mg/kg (n=15 patients). Plaque volume was measured before treatment and within two weeks after the final infusion using intravascular ultrasound (IVUS). With IVUS, a tiny ultrasound probe is inserted into the coronary artery to directly image and measure the size of the atherosclerotic plaques. The study revealed a statistically significant reduction (p=0.02) in percent atheroma (plaque) volume in the combined ETC-216 treatment groups comparing end-of-treatment values to baseline values.
Additional IVUS endpoints in the trial, such as total atheroma volume and maximum atheroma thickness, also showed statistically significant improvements.
"This study shows that ETC-216 could become an important new option for the treatment of people affected by atherosclerosis," said Steven E. Nissen, M.D., F.A.C.C., principal investigator of the study and medical director of the Cleveland Clinic Cardiovascular Coordinating Center. "We now have evidence that it is possible to rapidly and directly reverse the atherosclerotic disease process in artery walls."
Eventually in the much longer term (10 to 20 years is my guess) we can expect to see a gene therapy developed to deliver ApoA-I Milano protein gene into the liver of the vast bulk of us who do not have this beneficial variant of the gene (Update: the more likely scenario would be to just add more of the regular ApoA-I that would be expressed at a higher level to raise normal blood HDL levels). That way the benefit would be there all the time. To derive an even bigger benefit the gene therapy could also deliver a genetic variation Cholestryl Ester Transfer Protein (CETP) variant that makes cholesterol molecules bigger and extends life as a result.
Esperion's web site explains the mechanism of action.
The RLT pathway is a four-step process responsible for removing excess cholesterol and other lipids from the walls of arteries and other tissues, and transporting them to the liver for elimination from the body. The first step is the removal of cholesterol from the walls of arteries by HDL in a process called "cholesterol removal". In the second step, cholesterol is converted to a new form that is more tightly associated with HDL as it is carried in the blood; this process is called "cholesterol conversion". The third step is the transport and delivery of that converted cholesterol to the liver in a process called "cholesterol transport". The final step is the transformation and discarding of cholesterol by the liver in a process known as "cholesterol elimination". We believe our product candidates have the potential to enhance the effectiveness of these four steps in the RLT pathway in humans.
In a healthy human body, there is a balance between the delivery and removal of cholesterol. Over time, however, an imbalance can occur in our bodies in which there is too much cholesterol delivery by LDL and too little removal by HDL. When people have a high level of LDL-cholesterol, or LDL-C, and a low level of HDL-C, the imbalance results in more cholesterol being deposited in arterial walls than being removed. This imbalance can also be exaggerated by, among other factors, age, gender, high blood pressure, smoking, diabetes, obesity, genetic factors, physical inactivity and consumption of a high fat diet. The excess cholesterol carried in the blood in LDL particles can be deposited throughout the body, but can frequently end up in the arterial walls, especially those found in the heart. As a consequence, repeated deposits of cholesterol called plaque can form and possibly narrow the arteries, which may lead to acute chest pain (i.e. angina) or a heart attack. These are known as the "acute coronary syndromes".
As more genetic variants that affect health and longevity are found look for attempts to basically take "best of breed" genetic variations and stuff them all into each person who wants them. A lot of genes are expressed in only certain parts of the body and it may be practical to, for instance, upgrade livers to make better blood proteins. The eventual development of the ability to easily grow new replacement organs will facilitate this trend as people will get organs replaced with younger organs and in the process will opt to get genetic improvements added to the starter cells used to grow their new replacement organs.
A second but obvious choice would be to simply give people H.D.L., infusing it into their veins. But there was a problem. The idea of giving ordinary H.D.L. was in the public domain and was not protected by patent, and so companies were not interested.
There was, however, one H.D.L. that had been patented, and Dr. Roger Newton, the president and chief executive of Esperion Therapeutics, a small company in Ann Arbor, licensed the rights to develop it.
Rader noted that there could be nothing particularly special about this particular form of HDL. It could be that it's the only one that's been tested this way because it's a form of HDL that can be patented. Other companies are developing different ways of using HDL to fight heart disease, such as drugs that boost the body's own production of HDL.
So this therapeutic approach works simply by raising the amount of apoA-I, which is a component of HDL cholesterol molecules.
This illustrates a real serious problem in the development of new treatments: if the infusion of naturally occurring compounds produced by the body is not going to be pursued all that vigorously because most of the compounds are not patentabe then the rate of advance of new and very useful therapies will be much slower. The fact that apoA-1Milano happened to have been patented (perhaps before US patent laws changed to make it harder to patent human genes?) turns out to be very beneficial to us all in this case because it provided an incentive for a company to pursue the various rather expensive phases of animal and human trials.
Perhaps what is needed is some regulatory category for drugs that functions as a proxy for a patent that provides sole ability to sell a compound for some period of time of a company takes the time to go thru regulatory approval steps.
Update II: The Cleveland Clinic has also done recent work on injecting into the heart cells that express stromal cell derived factor-1 (SDF-1) so that the SDF-1 will instruct stem cells to repair the heart.
Previous studies have indicated that damaged heart muscle could be regenerated by directly injecting stem cells into the bloodstream or by chemically mobilizing stem cells from bone marrow either prior to a heart attack or within 48 hours afterward. At The Cleveland Clinic, Dr. Penn and his colleagues looked at the potential of stem cells in repairing hearts weeks after a heart attack, during congestive heart failure. To determine whether SDF-1 was sufficient to induce stem cell homing and recovery of heart function, investigators transplanted cells that expressed SDF-1 into hearts eight weeks following a heart attack. Their research showed that re-establishing SDF-1 expression in the heart led to the homing of circulating stem cells to the injured organ, the growth of new blood cells and the recovery of cardiac tissue. Reintroducing SDF-1 to the heart yielded nearly a 90 percent increase in heart function compared to hearts treated with cells alone. Just increasing the number of circulating stem cells using drugs that induce stem-cell mobilization eight weeks after a heart attack was not enough to initiate meaningful tissue regeneration, supporting the notion that repair to the damaged tissue is possible for only a limited amount of time following the heart attack. Finally, this research suggests a clinically viable strategy for delivering this molecule that can be tested in future trials involving other organ systems.
Note also that the natural, presumably unpatentable, form of Apo-A1 has been tweaked and modified quite a bit in its clinical studies. There are, I should think, eminently patentable processes there. Anyone, for example, who found a way to get around the purification difficulties of the native protein would patent the method immediately, and they'd get it, too. Any nonobvious formulations or dosing methods would be patentable - just find one that works. And I haven't even mentioned all the peptide analogs that people have been making - patentable, every one of 'em.
Update III: A September 26, 2004 report claims that the Catholic Medical Center in Manchester New Hampshire expects to be participating in the next round of Pfizer's ApoA-I Milano clinical trials which have been temporarily delayed for a reorganization.
Dr. Mary McGowan is director of the Cholesterol Management Center at CMC’s New England Heart Institute. She explained the company that developed the treatment— known as ApoA-I Milano — has since been purchased by the pharmaceutical giant Pfizer, and that has temporarily delayed the start of clinical trials while the company is reorganized.
McGowan said the NEHI has worked on cholesterol studies with Pfizer in the past. And she said last week, “I think there’s very little doubt that we’ll be working with ApoA-I Milano.”
Most clinical trial enrollments are done through the medical centers conducting the trials. So readers would be better off contacting the Cleveland Clinic or the Catholic Medical Center in hopes of getting in on the next round of trials.
The ability to detect cancer at ever earlier stages using advances in blood and other testing will combine with the coming ability to grow replacement organs to provide a better method for treating some forms of cancer: organ replacement.
Alexandria, VA-In the first national study to examine survival among liver transplant patients with advanced hepatocellular carcinoma (HCC), researchers found excellent five-year survival results, with a steady improvement over the last decade. Hepatocellular carcinoma, also known as hepatoma, or cancer of the liver, is a common cancer worldwide, with more than one million new cases diagnosed each year and a median life expectancy of six to nine months. Most hepatoma patients have cirrhosis, a risk factor of hepatoma, and are inoperable because of tumor size, location or severity of underlying liver disease. Results of this study will be reported online in the Journal of Clinical Oncology."This study shows that we can achieve excellent survival with liver transplantation among patients with hepatoma, confirming similar results reported by single center studies," said Paul J. Thuluvath, MD, senior author and Associate Professor in the Department of Medicine at Johns Hopkins University School of Medicine. "These findings are particularly reassuring for patients with tumors that cannot be surgically removed, which comprise more than 80 % of HCC patients."
The results for this approach are good and improving:
Researchers found significant and steady improvement in survival over time among liver transplant patients with HCC, particularly in the last five years. Five-year survival improved from 25.3 percent during 1987-1991 to 47 percent during 1992-1996, and 61.1 percent during 1996-2001.
Of course, the big problem is that there are not enough donor organs. The future development of the ability to rapidly grow replacement organs will yield a very attractive option for many forms of organ cancer: replace the defective part. Why not? After all, if you are 50 or 60 or 70 years old replacement of a tired old organ with a lot of miles on it could provide a bit of a boost. Preemptive replacement of many old organs before an organ cancer even begins would partially reverse aging. Put in a new stomach, intestines, liver, pancreas and other parts to get a late middle age partial rejuvenation while simultaenously reducing the risk of cancer.
STANFORD, Calif. Bone marrow cells can fuse with specialized brain cells, possibly bolstering the brain cells or repairing damage, according to research from the Stanford University School of Medicine. This finding helps resolve an ongoing debate: Do adult stem cells transform from bone marrow cells into other cell types, such as brain, muscle or liver cells, or do they fuse with those cells to form a single entity with two nuclei? The research shows that for complex brain cells called Purkinje cells, fusion is the normal pathway.
Helen Blau, PhD, the Donald E. and Delia B. Baxter Professor of Pharmacology, had previously shown that transplanted bone marrow cells can wind their way up to the brain in humans where they take on characteristics of Purkinje cells – large cells in the part of the brain that controls muscular movement and balance. She had also shown that mature cells in a lab dish can fuse with other cell types and take on characteristics of those cells.
In her most recent work, published in the Oct. 16 advance online issue of Nature Cell Biology, Blau showed that the bone marrow cells in mice fuse with existing Purkinje cells and activate genes normally made in Purkinje cell nuclei. The work will also be published in the November issue of the journal.
“I think that fusion might be a really important biological mechanism,” Blau said. She said researchers previously considered fusion to be less medically important than the idea that bone marrow cells may be able to change fates entirely. Blau disagrees with that assessment. “Fusion might be a sophisticated mechanism for rescuing complex damaged cells,” she said.
Blau and senior research scientist James Weimann, PhD, transplanted mice with bone marrow cells that had been genetically altered to produce a fluorescent green protein. Over the course of the next 18 months (75 percent of a mouse’s life span), they looked for signs of fluorescent green cells in the animals’ brains.
Over time, the group found an increasing number of Purkinje cells that glowed green under a microscope. Looking closely at these cells, they found two nuclei – one from the original Purkinje cell and one from the fused bone marrow cell. They also found that the compact nucleus of the bone marrow cell expanded over time to take on the appearance of the more loosely packed Purkinje cell nucleus.
The Stanford researchers want to develop a better understanding of the signalling process that causes a stem cell to merge with a Purkinje cell in order to be able to find ways to encourage stem cells to merge with damaged brain cells in patients suffering from neurological disorders.
This process of stem cell merger with brain cells also opens up the potential for use of stem cells as a way to deliver better genetic programming in order to do cognitive enhancement and to deliver genes that can undo the effects of aging. If stem cells can be genetically engineered to have genetic variations that enhance cognitive performance then at least some of the existing cells in the brain will be able to be enhanced with genetic variations that will be identified in the future as contributing to intelligence and other aspects of brain function.
There is also an obvious application for trying to reverse some of the general aging of the brain. Genomic decay that occurs with aging could be dealt with at least in part by sending in stem cells to deliver younger nuclei to aged brain cells. Those younger stem cells could also deliver additional genes that would help to basically refurbish aged brain cells. One potential class of genes that could be delivered via this mechanism would be lysosomal enzymes (lysosomes are intracellular organelles that break down waste material in a cell) from other species that are capable of breaking down accumulated intracellular junk that human lysosomal enzymes are unable to break down.
Update: This research is also important because it suggests that adult stem cells may have less potential to differentiate into various cell types than was previously thought.
The adult bone marrow cells appear to fuse with existing cells of the heart, liver and brain rather than differentiating into entirely new ones, the scientists said. The studies suggest that only embryonic cells have the potential to regenerate diseased tissues.
Researchers who were involved with this research caution that clinical trials using adult stem cells are proceeding on a questionable assumption about how those stem cells work. Arturo Alvarez-Buylla of the University of California, San Francisco say past results may have mistakenly been interpreted as evidence of differentiation when fusion was really at work.
According to Morrison and Alvarez-Buylla, their findings offer caution to researchers who have already begun clinical trials in which they are inserting bone marrow cells into damaged heart tissue, in an attempt to regenerate healthy muscle.
"Our findings raise a red flag about going too fast to clinical trials based on the assumption that transdifferentiation is the mechanism by which stem cells give rise to other cell types," said Alvarez-Buylla. "Our paper suggests that previous claims of transdifferentiation may be explained by cell fusion." The scientists said they cannot rule out that transdifferentiation might be occurring, but that they saw no evidence of it in their experimental system.
But if any on-going clinical trials using adult stem cell injection find benefits for people with, for instance, heart disease then it is unlikely the patients will complain just because the benefit comes via a mechanism different than the original mechanism on which the trials were originally justified. There are lots of people with very sick hearts and months left to live who are probably very willing to gamble.
Eventually methods will be developed that will allow cells to be instructed to shift between various types of cells regardless of the starting cell type. Advances in the ability to assay methylation patterns on DNA will allow the tracking of epigenetic state changes and the more rapid development of techniques for causing and controlling the transition of cells into different cell types.
Dr. Neil A. Williams of the University of Bristol in Britain and colleagues are working on a vaccine made from a protein found in an E. coli bacteria strain that trains the immune system to stop auto-immune responses.
In a study of a strain of mice that naturally develop diabetes, the vaccine, which is being developed with the backing of British biotech company Hunter-Fleming Ltd, reduced the occurrence of the illness from 80 to 15 percent.
Auto-immune responses play a role in rheumatoid arthritis, type I diabetes, multiple sclerosis, allergies, asthma, and a number of other disorders.
The Escherichia coli bacteria's Enterotoxin B Subunit which makes up this vaccine is known as ETxB.
The team is using just a transport component of the bacterium's toxin molecule. Called ETxB, the component is separated off from the rest of the protein so there is no chance of a vaccine causing stomach upsets in patients.
The vaccine reduced the incidence of type 1 diabetes in mice strains prone to the disease from 80 per cent to 15 per cent. Arthritic mice show similar benefits. Williams is now collaborating with the pharmaceutical company Hunter Fleming to conduct the first human trials, which should begin in six months.
A model of how ETxB stops auto-immune response is available here.
This is pretty special. If a single vaccine could eliminate or even just substantially reduce the frequency of a wide range of auto-immune disorders the benefits would enormous.
"About one in a million T-cells holds latent HIV that the antiretroviral drugs can't touch," said Zack, a professor of medicine and vice chair of microbiology, immunology and molecular genetics at the David Geffen School of Medicine at UCLA. "Our challenge was to make latent HIV vulnerable to treatment without harming healthy cells."
The UCLA researchers created a model using mice specially bred without immune systems. The team implanted the mice with human thymus tissue and then infected the tissue with HIV. The mice responded by producing human T-cells infected with latent HIV.
Zack and Brooks next used a two-step approach to expose and destroy latent HIV. First, they stimulated the T-cells strongly enough to prompt the cell to express latent virus but not to trigger other cellular functions. This revealed the hidden HIV.
Second, they used a new weapon called an immunotoxin — an anti-HIV antibody genetically fused with a bacterial toxin — to target and kill only the T-cells infected with HIV.
"The immunotoxin functions like a smart bomb — the antibody is the missile guidance system and the toxin is the explosive," Zack said. "When the T-cell switches on and starts expressing virus, the antibody binds to the surface of the T-cell, forcing the toxin into the cell and killing it. This prevents the cell from making more virus."
"The beauty of this approach is that it doesn't destroy healthy T-cells — only the ones hiding virus," Brooks said.
Prior to the UCLA discovery, scientists needed to over-stimulate T-cells to force them to express latent virus. This ran the risk of harming the patient by impairing the entire immune system. In contrast, the UCLA model exposed and killed hidden HIV without affecting the rest of the immune system. The T-cells in the UCLA model also did not divide, indicating that they were able to produce virus without behaving as if they were confronting a foreign particle.
"In our mouse model, the two-step approach cleared out nearly 80 percent of the latently infected T-cells," said Zack. "No one has ever been able to achieve this before. We hope that the strategy we've proven effective in the lab will show similar success in people."
This technique still must undergo a lot of development before it is ready for use in humans. One difficulty will be to be able to calibrate how exactly to stimulate human T-cells just enough to get only the desired response. Given that lab animals are less genetically variable than humans the discovery of the correct level of stimulation may be hard to do for each patient. Also, there are plenty of other factors that could make the results harder to duplicate in humans. Still, this is a clever technique.
Humans suffer from a number of other chronic viral infections including oral and genital herpes and various forms of viral hepatitis. The ability to eliminate chronic viral infections would be great for the wider population as well. However, this model doesn't really work for them since this model is specific to T-cells which HIV infects. Still, it does not seem unreasonable to expect that ways will also be found to bring viruses out of hiding in other cell types.
Stem cells isolated from human embryos were injected into rats suffering from neuronal damage caused by a virus. The stem cells helped recover movement by releasing growth factors that helped the damaged neurons to recover.
In their experiments, spearheaded and majorly funded by the private organization Project ALS, the scientists first infected rats with a virus (Sindbis) they developed that selectively destroys nerve cells that control muscles in the hind limbs. Lou Gehrig's disease, also known as ALS or amyotrophic lateral sclerosis, is similarly marked by a gradual loss of the nerves that control muscles, although its cause is unknown.
One-third of the animals then received transplants of human embryonic germ cells, which are capable of becoming any cell type, into their spinal fluid. The other rats served as controls and received either hamster kidney cells or human cells that don't have stem cell properties.
Twelve weeks later, the 15 paralyzed rats that got human stem cells partially recovered control of their hind limbs. Moreover, their hind limbs were 40 percent stronger than control animals'. By 24 weeks, 11 of the 15 turned over at least three seconds faster when placed on their backs than before getting the human cells. Control rats did not improve, on average, over the 24 weeks of the study.
In paralyzed rats, Kerr and his team found that most of the implanted human cells migrated into the spinal cord, and many became cells of the nervous system -- astrocytes, neurons and even motor neurons -- while in uninjured animals the transplanted cells just sat on the spinal cord's outer surface. However, even in injured animals, only about four human cells per rat became motor neurons that actually extended out of the spinal cord and into muscle, potentially creating a circuit that could control movement.
"We saw some physical recovery, and we saw human stem cells that had become motor neurons, but it turns out that the two observations weren't related," says Kerr. "We saw functional recovery that wasn't due to new neurons, and we had no idea how that could be possible."
Kerr then discovered that the rats' own neurons were healthier in animals that received human stem cells. In subsequent laboratory experiments, Kerr found that the human stem cells produced copious amounts of two key growth signals. These were transforming growth factor-alpha (TGF-alpha), which promotes neurons' survival, and brain derived neurotrophic factor (BDNF), which strengthens their connections to other neurons. When the scientists blocked these two signals in the laboratory, the stem cells' beneficial effects disappeared.
"Even before motor neurons die, connecting neurons peel back as if they sense a sinking ship," says Kerr. "Simply keeping a neuron alive can't improve physical abilities if it's not connected to other neurons. It must be part of a circuit.
"In some ways our results reduce stem cells to the non-glamorous role of protein factories, but the cells still do some amazing, glamorous things we can't explain," he adds. "For example, the white matter that surrounds the spinal cord was thought to be an impenetrable barrier to axon growth, but some of the transplanted cells not only migrated into the spinal cord, but also sent axons back out. It is just incredible."
This is the second study to come out in the last couple of weeks that showed a beneficial effect from stem cells where the stem cells worked their benefit by releasing compounds that transformed other existing cells. The other was the use of bone marrow stem cells to restore insulin production to existing pancreatic cells. These are surprising results.
These two sets of results suggest that in addition to serving as a supply of new cells to replace damaged or lost cells a normal function of stem cells may be to supply signals to encourage growth and change of cell type in existing non-stem cells.
These results also make me think that the therapeutic value of stem cells as growth factor delivery vehicles could be enhanced by genetic engineering. If stem cells are needed to deliver a particular growth factor or set of growth factors then their effects might be able to be enhanced by genetically engineering them to produce more of whichever growth factors are needed for a specific therapeutic purpose. Damaged neurons need different growth factors than damaged pancreatic cells for instance. So it makes sense to use gene therapy to program stem cells to produce the exact growth factors needed for each purpose.
A research team at the Robarts Research Institute in London Ontario Canada led by Dr Mickie Bhatia has successfully used bone marrow stem cells to regenerate damaged pancreases in diabetic mice to cure their diabetes.
The scientists injected bone marrow stem cells into diabetic mice, who were cured or back to normal within seven to 14 days.
But the "most amazing" finding, said Bhatia, is that the stem cells triggered the rodents' damaged pancreases to regenerate on their own.
Here's the surprising part: the stem cells did not integrate into the pancreases of these mice. Instead they somehow triggered the pancreatic cells to become insulin-producing cells. Bhatia's group is now searching for molecules that the bone marrow stem cells might have released to induce the pancreatic cells to repair the damage to the pancreas.
When the researchers injected stem cells into mice with pancreatic damage, the organs were stimulated to repair themselves within 17 days.
Type I diabetes takes literally decades off life expectancy. The greater range of swings in blood sugar that diabetics experience causes their bodies to develop degenerative diseases of old age more rapidly. A human version of this treatment would be very beneficial. If molecular signals are released by the stem cells and can be identified then just those chemicals could be used as therapeutic agents to cure diabetes.
Diamyd Medical's phase II trial was conducted on 47 diabetes patients with the GAD‑based vaccine at the UMAS hospital in Malmoe, Sweden, and St. Gorans Hospital in Stockholm, Sweden. The patients were randomly divided into four groups of approximately 12 patients per group. Each patient received one injection of the vaccine, followed by at least one boost injection four weeks later. Nine patients in every group received the active drug; three received placebo. The groups received different doses of the vaccine, ranging from 4 micrograms to 500 micrograms per dose.
All patients visited the hospitals 10 times during this six-month study. Detailed clinical, immunological and neurological investigations showed no safety concerns at the administered dose levels. The study results show that the diabetes vaccine could significantly protect the patient's ability to secrete insulin, both when fasting and after meals.
The GAD vaccine originated at UCLA from an unexpected convergence of studies in neurobiology and immunology. In the late 1980s, the laboratory of Dr. Allan Tobin, who now directs the UCLA Brain Research Institute, was involved in isolating genes that were thought to be important in brain development and neurological diseases.
Working with Tobin, graduate students Kaufman and Mark Erlander isolated the gene that makes a protein called "GAD," which creates an important neurotransmitter in the brain. At that time, it was known that although GAD was made primarily in the brain, it was also made in the pancreas in the cells that secreted insulin.
Several years later, Kaufman and Tobin realized that the autoimmune response that causes type I diabetes may be due to the immune system attacking the GAD protein in the insulin-producing cells in the pancreas. With this knowledge, they developed a GAD diagnostic test for identifying individuals who were developing type I diabetes based on antibodies in their blood that recognized GAD.
Kaufman, in his own laboratory at the UCLA Department of Molecular and Medical Pharmacology, along with Dr. Jide Tian, of the same department, searched for ways to help the immune system tolerate the GAD protein, which would circumvent or inhibit the autoimmune attack.
The team reported in the journal Nature in 1993 that when young, diabetes-prone mice were treated with a small amount of the GAD protein, their immune systems learned to tolerate the protein. The autoimmune response that leads to type I diabetes never developed in these mice as they grew older.
In another study published by Nature-Medicine in 1996, the UCLA team developed the GAD vaccine to inhibit the autoimmune response after it had already begun to attack the insulin‑producing cells. Kaufman and Tian showed that even after the type I diabetes disease process had started in diabetes-prone mice, its progression could be inhibited by the GAD vaccine.
According to Tian, the GAD vaccine activated T-cells (a type of white blood cell or immune defense cell) that recognized GAD. The T-cells traveled to the pancreas and, recognizing the GAD protein, released calming substances called "anti-inflammatory" cytokines, which suppressed the immune cells that were killing the insulin-producing cells.
"The beauty of this vaccine is that it just affected one small part of the immune system — without broadly inhibiting the function of the entire immune system," Tian said.
For people who already have type I (the kind that comes when one is young) diabetes this is probably a necessary treatment in addition to a treatment that will get the pancreas producing insulin again. Otherwise a pancreas that starts producing insulin will likely come under auto-immune attack again.
Update: Also see a January 2004 report that reports how infection of mice with lymphocytic choriomeningitis virus (LCMV) in the early stages of diabetes stops the autoimmune response.
Viruses can both cause and prevent autoimmune disease. In order to understand this dualism, Matthias von Herrath and colleagues from the La Jolla Institute for Allergy and Immunology in California exposed prediabetic mice to viral infections. In the January 2 issue of the Journal of Clinical Investigation the authors report that infection with lymphocytic choriomeningitis virus (LCMV) during the prediabetic period completely abolished the diabetic process in two distinct mouse models.
This protection against the development of type 1 diabetes correlated with a reduced number of autoaggressive CD8 T cells in pancreatic islets. Increased production of the chemokine CXCL-10 in pancreatic lymph nodes redirected cells of the immune response away from the b cells. Once in the pancreatic lymph node, CD8 lymphocytes underwent increased apoptosis, which was directly dependent on TNF-a and indirectly on IFN-g production. The data indicate that proinflammatory cytokines and chemokines induced by viral infection can influence ongoing autoaggressive processes beneficially at the preclinical stage if produced at the correct time, location, and level. Therefore viruses that do not directly destroy b cells may actually enhance the course of autoimmune diabetes.
Age and exposure to loud noises can damage the inner ear cochlea hair cells that grow the fine cilia hair that are used to measure sounds. Recently some scientists at the University of Michigan have succeeded in using gene therapy delivered by adenovirus vector into the cochlea to add a gene called Math1 to cells in that area that stimulates those cells to become hair cells. Math1 gene theapy has resulted in the growth of hair cells in the cochlea and nerves were detected growing toward those hair cells.
Gene therapy grows new auditory hair cells in mammals ANN ARBOR, MI – University of Michigan scientists have used gene therapy to grow new auditory hair cells in adult guinea pigs – a discovery that could lead to new treatments for human deafness and age-related hearing loss.
Healthy hair cells are vital to the ability to hear, but aging, infection, certain medications and exposure to loud noises can damage or destroy hair cells causing sensorineural hearing loss – a condition affecting over 30 million Americans. Since the discovery, in the late 1980s, that birds can spontaneously regenerate damaged hair cells, scientists have been trying to find a way to induce the replacement of lost hair cells in mammals.
U-M scientists have now accomplished this goal by inserting a gene called Math1 into non-sensory epithelial cells lining the inner ear. Results from the study will be published in the June 1 issue of the Journal of Neuroscience.
"We found that non-sensory epithelial cells in adult guinea pig cochlea can generate new sensory hair cells following the expression of Math1," says Yehoash Raphael, Ph.D., an associate professor of otolaryngology in the U-M Medical School, who directed the study. "We also found that some of these hair cells can attract the growth of new fibers from auditory neurons."
In a normal ear, vibrations from sound waves striking the eardrum are transferred to fluid inside a snail-shaped bony organ called the cochlea, which is the auditory component of the inner ear. When cochlear fluid moves, it stimulates movement in thousands of tiny projections on hair cells lining the inside of the cochlea. Moving hair cells initiate electrical signals, which are picked up by auditory nerve fibers and carried to an area of the brain called the auditory cortex. If hair cells are damaged or missing, electrical signals are not generated and hearing is impaired.
"During the embryonic stage of an animal's development, hair cells and supporting cells have a common origin. Cells that express Math1 are fated to become hair cells, while Math1 expression is inhibited in the remaining non-sensory cells," Raphael says.
"After embryonic development, hair cell production ceases. Unlike other epithelial cells in the skin or gut, epithelia in the inner ear contain no stem cells, so there is no source for renewal," Raphael explains. "That's the main reason why hair cell loss is permanent. When we over-expressed Math1 in non-sensory cells of the mature cochlea, however, we found that it causes them to transdifferentiate or change their personality to become hair cells."
"We knew that transdifferentiation of supporting cells was a major source of new hair cell development in birds," Raphael says. "But there was no proof it would work in mammals. We started gene therapy experiments in 1994 and it took us seven years to develop a successful method of introducing the gene into the non-sensory cochlear epithelium."
Dr. Kohei Kawamoto, Ph.D., a former U-M research fellow who performed the laboratory experiments, used an adenovirus as a vector to deliver the Math1 gene to inner ear epithelial cells. Kawamoto injected the Math1 vector into inner ear fluid of 14 adult guinea pigs. The same procedure, but without the transfer of the Math1 gene, was performed on 12 matched control animals.
Thirty to 60 days after inoculation, U-M scientists used scanning electron microscopes to examine inner ears from both sets of animals. In experimental guinea pigs that received the Math1 gene, scientists found new hair cells growing in areas where hair cells are typically absent. No new hair cells were found in the control animals.
"The inner ear is an ideal target for gene therapy, because it is closed – not sealed, but nicely isolated," Raphael says. "As long as the amount you inoculate is small, the spread to other organs is minimal, and the risk of systemic toxicity is almost zero."
Because the total amount of fluid in the inner ear of a guinea pig is so small, the mechanical impact of injecting the viral vector fluid into the cochlear fluid damaged some of the hair cells in experimental animals. "While this is a concern, we believe the micro-injection technology can be improved to prevent this mechanical trauma," Raphael says. "The human cochlea is larger than a guinea pig cochlea and may better tolerate the inoculation. Also, profoundly deaf human candidates for this gene transfer approach would likely have severe pre-existing hair cell loss to begin with, so the risk of mechanically-induced side effects would be somewhat less troubling."
One of the most surprising results of the study was the discovery of long, slender nerve fibers growing toward some of the newly formed hair cells. "This suggests that these hair cells can provide signals to attract axons and that neurons can respond to these signals," Raphael says.
In the next stage of research, Raphael will determine whether the guinea pig hair cells are functional and able to transmit sound signals to auditory neurons. He also plans to test the procedure in aging animals and in animals that are completely deaf.
"This is just the beginning," Raphael says. "It is really just a proof of the principle to show that, with proper gene therapy, these non-sensory cells have the competence to become hair cells."
The research was funded by the National Institute on Deafness and Other Communication Disorders of the National Institutes of Health and supported by GenVec, Inc. GenVec provided its proprietary adenovector technology to deliver the atonal gene, Math1. Raphael was an occasional consultant to GenVec, but has no significant financial interest in the company.
First author on the paper was Kohei Kawamoto, Ph.D., a former U-M research fellow who is now at Kansai Medical University in Osaka, Japan. Co-authors on the paper include Douglas E. Brough, Ph.D., director of vector sciences at GenVec, Inc.; Shin-Ichi Ishimoto, Ph.D., a former U-M research fellow; and Ryosei Minoda, Ph.D., a post-doctoral fellow in the U-M Medical School.
This result demonstrates how gene therapy can be used to repair one kind of damage caused by injury and aging. It will take several years to turn this into a safe and useful human gene therapy. However, it seems likely that within 10 or at most 20 years deafness caused by cochlea hair cell death will be a curable disorder.
A recent report about the benefits of the higher level of an enzyme provides a candidate for the use of gene therapy to reduce the risk of heart disease and of other illnesses associated with old age. Activity of an enzyme called paraoxonase can reduce the risk of heart attacks.
DALLAS, May 20 – An oxidation-fighting enzyme called paraoxonase (PON1) can significantly reduce the risk of heart attacks, according to research reported in today’s rapid access issue of Circulation: Journal of the American Heart Association. The enzyme attaches itself to high-density lipoprotein (HDL), which is known as “good” cholesterol. When PON1 is highly active, the risk for heart attack is cut by 43 percent, says study author Michael Mackness, Ph.D., of the University Department of Medicine, Manchester Royal Infirmary, Manchester, United Kingdom.
Postprandial peaks in plasma concentration of lipid hydroperoxides (in laymans terms: a boost in free radicals in fats in the blood after meals caused by the generation of fat free radicals in the gut during digestion) are theorized to contribute to the development of atherosclerosis and to the risks of heart disease and stroke. It is even possible that the boost in blood free radicals after each meal contributes to the general aging of the body. Peroxonase is probably working by breaking down lipid hydroperoxide free radicals into compounds that are less harmful to the body. More peroxonase attached to HDL cholesterol in blood serum probably causes the more rapid breakdown of lipid hydroperoxides after meals and therefore reduces the amount of cumulative damage that they cause.
The authors of this research paper state that if a dietary change or drug could boost PON1 activity then it is likely this would reduce the risk of heart disease and stroke. But a more permanent solution would be to do gene therapy to increase the blood levels of PON1. Researchers at University of Texas Southwestern Medical Center have already developed an experimental gene therapy for boosting paraoxonase levels.
Those veterans who have suffered brain damage from OP exposure during the war express significantly lower levels of PON, type Q, than those soldiers who remained well after the war. Other research has shown that these polymorphisms may also be involved in the development of Parkinson's Disease, amyotropic lateral sclerosis, and atherosclerosis. The inventors have developed gene therapy vectors that can be introduced into humans to boost their levels of PON and may lead to effective treatments to combat or prevent the aforementioned conditions.
There has been a lot of previous research into the role paraoxonase plays as an antioxidant in the blood.
The data are consistent with the hypothesis that lower expression of this anti-oxidant enzyme increases risk of coronary disease. Ageing has also been identified as an independent determinant of serum paraoxonase levels. Ageing is correlated with reduced serum paraoxonase levels, which may compromise the protective influence of enzyme. The results are consistent with the contention that the protective, anti-oxidant capacity of high density lipoproteins is at least in part genetically determined.
Gene therapy to raise paraoxonase might be useful for those younger people who have genetically low levels of paraoxonase. But note that since paraoxonase declines with age even people who have high levels of paraoxonase in their youth and middle age might benefit from gene therapy to boost paraoxonase as they age.
The reason for this post is to make a larger point: it may seem depressing to know that you probably have genetic variations that increase your risk for a variety of illnesses and that cause you to grow older faster. But a more optimistic way to see all the genetic risk factors that are being discovered is that future candidates for gene therapy are being identified. As more details are filled in about how different genetic variations contribute to development of diseases many potential benefits of future gene therapies are becoming better understood.
Is it realistic to expect that the effects of the deleterious genetic variations can be dealt with using gene therapies? Well, one reason to have that more optimistic view is that many genes are expressed only in a single organ or their role in the development of particular diseases is due to their effects in a single organ. Therefore gene therapy doesn't have to be able to reach every cell in the body (which would be incredibly hard to do) in order to be beneficial. In the case of paraoxonase the concentration of it in the blood is probably coming from synthesis in the liver followed by excretion into the blood. Therefore a gene therapy aimed at boosting blood paraoxonase only has to reach some cells in the liver. Another possibility would be to do gene therapy to stem cells that are capable of becoming liver cells. But the point is that gene therapy has to reach only a fairly small fraction of the body's cells in order to reverse the effects of an unfortunate inherited predisposition to disease. Your genetic inheritance does not have to dictate your health destiny.
It is very gratifying when some researchers working on something less important like cancer research accidentally hit upon a discovery for how to deal with a far more important medical problem: male pattern baldness.
“Other researchers have shown that beta-catenin and other genes in the Wnt (“wint”) pathway are important for normal development of hair follicles in embryos and after birth,” says Dlugosz, an associate professor of dermatology in the U-M Comprehensive Cancer Center. “What’s new about our study is the finding that a brief activation of beta-catenin in resting hair follicles could be enough to trigger the complex series of changes it takes to produce a normal hair.”
The original purpose of the research study was to learn how the Wnt signaling pathway and beta-catenin are connected to cancer development, according to Fearon, the Emanual N. Maisel Professor of Oncology in the U-M Cancer Center. “Beta-catenin carries signals from growth factors called Wnts to the cell’s nucleus,” Fearon says. “If beta-catenin expression in the cell isn’t adequately controlled and regulated, it changes normal patterns of gene expression. This can lead to several types of cancer, especially colon cancer.”
The study used genetically altered mice developed in the U-M Transgenic Animal Model Core. By adding a packaged set of genes called a construct to fertilized mouse eggs, U-M researchers created a new strain of transgenic mice with an inducible form of beta-catenin in their skin cells and hair follicles.
Van Mater induced beta-catenin signaling activity by applying a chemical called 4-OHT to shaved areas on the backs of the transgenic mice and matched control mice with normal beta-catenin genes. This chemical turned on the beta-catenin in the skin and follicles of the transgenic mice. The plan was to use 4-OHT to turn on beta-catenin activity in the transgenic mice until skin tumors developed, and then turn off beta-catenin activity to see if the tumors disappeared.
“But we never saw tumors -- just massive hyperplastic growth of hair follicle cells,” Van Mater says. The scientists also noticed other skin changes that suggested an exaggerated growth phase of the hair cycle. Dlugosz suggested applying 4-OHT just once, instead of every day, and to do it during the hair follicles’ resting phase or telogen.
“Hair follicles are like a mini-organ in the body,” explains Van Mater, a graduate student in the U-M Medical School’s Medical Scientist Training Program. “Unlike most organs in the adult body, hair follicles go through regular cycles of growth, regression and rest. They are able to regenerate completely during each growth phase. Previous studies had suggested that a Wnt signal might be the switch that drives resting hair follicles into the active growth phase. By treating the transgenic mice with a single application of 4-OHT, we hoped to mimic the effect of a short pulse of Wnt expression in normal mice.”
So Van Mater started over -- applying 4-OHT just once to the shaved backs of transgenic mice and normal mice during the telogen phase of the hair cycle. Fifteen days later, the transgenic mice needed another shave, but there were no signs of new hair growth on the control mice.
“Our findings suggest some potential strategies for inducing hair growth, but it is premature to think these results will lead to new approaches for treating common male-pattern baldness,” Dlugosz cautioned. “Many hair follicles in bald and balding men are greatly reduced in size, so merely reactivating hair growth would not produce a normal hair. Also, activation of beta-catenin in the body would need to be tightly regulated, since uncontrolled beta-catenin activity can lead to tumors of hair follicle cells or tumors in other sites, such as the colon, liver or ovary.”
These cautious researchers are reluctant to see their discovery used to reverse hair loss because the treatment might cause cancer. Of course this just makes it more important to discover a cure for cancer. If safe and reliable treatments to quickly kill cancer cells were available then any side-effects of curing baldness could be dealt with.
Scientists at Baylor College of Medicine have developed a gene therapy that causes liver cells to convert into insulin producing beta cells which normally are found only in Islets of Langerham in the Pancreas.
HOUSTON (April 21, 2003) – A gene therapy developed by researchers at Baylor College of Medicine has apparently cured diabetes in mice by inducing cells in the liver to become beta cells that produce insulin and three other hormones.
"It's a proof of principle," said Dr. Lawrence Chan, professor of medicine and molecular and cellular biology as well as chief of the division of diabetes, endocrinology and metabolism at the College. "The exciting part of it is that mice with diabetes are 'cured.' "
In the research, which is described in a report in Nature Medicine's online edition today, Chan and his colleagues used the NeuroD gene, a transcription factor that induces the liver to produce cells that make insulin and the three hormones associated with the pancreas' endocrine system.
The gene was attached to a so-called "gutless" adenovirus from which all toxic genes had been removed. This viral vector is a very efficient way to introduce genes into liver cells. Alone, NeuroD partially corrected the disease in the diabetic mice. Combined with a beta cell growth factor called Btc, the gene therapy complete cured the mice's diabetes for at least four months.
An added benefit is that the cells in the liver also produce glucagon, somostatin and pancreatic polypeptide, which may play a role in controlling insulin production and release.
"Until now it has not been possible to induce the formation of islets by any gene therapy approach," said Chan.
It does not mean that the treatment can be used in people immediately.
"It's farther from people than I would like," he said. He knows of no stumbling blocks to its effectiveness in people.
The main stumbling block is the vector or virus used to take the gene into the cells. Chan and his colleagues used the safest viral vector available today, but he expects even safer ones to be available within the decade.
"We want to use the safest vector possible," he said.
The treatment has advantages over transplant of islet cells, the insulin producers in the pancreas, because it avoids the lifelong use of powerful immunosuppressive drugs and eliminates the need to find a compatible donor.
Chan credits one of his postdoctoral students, Dr. Hideto Kojima, with much of the work in developing this protocol.
A UPI article about this report says this treatment does not permanently cure diabetes.
However, this "cure" is temporary and would require repeated injections, researchers point out. Also, just because this worked very well in mice does not guarantee such effects in people. "Unfortunately, it will probably take years," before such a treatment would be available to diabetes patients, Chan said. "Like any other gene therapy, the major concern is safety. People are quite different than mice.
The UPI article is the only article on this story that makes this claim that treatment does not last indefinitely. It seems odd. If cells are induced to differentiate into a different cell type I'd expect the new cell type state to be stable. Also, this treatment has already worked for 4 months in these mice. How long does it take for the treatment to wear off? It is possible that the NeuroD genes added to cells gradually break down and when they stop being expressed then all the downstream effects they cause in the cells stop happening.
Even if the injections had to be periodically repeated they'd still be an enormous boon for sufferers of Type I diabetes. Not only would diabetics be freed from daily injections, blood tests, and carefully regimented diets but they'd also live longer and healthier lives.
In the longer run gene therapies will improve to allow genes to be added to cells in ways that cause those genes to stay around permanently. Ways will be developed to deliver stable plasmids into cells and those stable plasmids will carry the desired genes.
My guess is that within 10 to 15 years type I diabetes will be a curable disease. If the genes used in this latest work have the same effect on human liver cells then the biggest remaining obstacle will be the development of better gene therapy vectors to deliver genes safely into cells. That's a topic that is seeing a great deal of work and it seems reasonable to expect better and safer gene therapy delivery methods will be developed within several years.
The use of ultrasound microbubble gene therapy to successfully deliver genes into muscles in mice raises hopes of use of this technique to treat muscular dystrophy.
Scientists at the Hammersmith Hospitals NHS Trust, Imperial College London and the Medical Research Council have pioneered a new way of delivering gene therapy, using an innovative combination of ultrasound and microbubbles. Research published today (20th February 2003) in Gene Therapy1 shows how this new delivery technique not only improves the efficiency of modifying genes, but may offer safety advantages over other methods.
Gene therapy has the potential to treat or cure many diseases where there is an underlying genetic cause, but its progress has been severely hampered by concerns over the way in which genes are delivered. There are a number of safety and other issues surrounding the use of viruses and existing non-viral techniques have proved to be less effective.
Dr Martin Blomley (Senior Lecturer in Radiology) and Dr Qi-Long Lu (Senior Research Scientist), together with Dr Haidong Liang (Research Associate) and Professor Terry Partridge at the Hammersmith Hospitals NHS Trust, Imperial College London, and the Medical Research Council Clinical Sciences Centre, have been developing this new gene delivery technique. They have been studying skeletal muscle in mice, which gives insight into how we might use gene therapy to treat muscular dystrophy in children.
Microbubbles are already in use around the world to improve patient ultrasound scans in the heart, liver and many other areas and are known to be both safe and effective. They are tiny gas bubbles measuring about 3 microns, and are usually injected intravenously to boost ultrasound signals. There is evidence that when ultrasound is applied to microbubbles the microbubbles are disrupted (or "pop") and this can cause small perforations in the target cells, which allows the DNA to enter. This could allow for a "point and shoot" approach, as ultrasound can be pointed at a particular target area.
The Hammersmith Hospital, together with Imperial College, is a leading international centre for the use of the use of microbubbles in imaging and is also at the forefront of research into gene therapy.
The researchers mixed a commercial microbubble, already used by doctors for scanning patients, with DNA that coded for a "reporter gene" and injected it into the skeletal muscle of mice of different ages. The trial showed that the microbubbles and ultrasound helped in delivering DNA, and the efficiency of gene therapy was improved by about ten times. They also observed that even when the microbubbles were used without ultrasound, an improvement in efficiency could be seen, especially in younger mice. In younger mice, no additional improvement in efficiency was conferred by using ultrasound. In addition, in experiments where microbubbles were used, the amount of inflammation and damage associated with the injection was reduced.
Overall results from the trial, which was supported by the Medical Research Council, showed:
- Microbubble ultrasound improved the delivery of DNA to the muscle
- The microbubbles have some effect intrinsically and may reduce local inflammation
As non-viral methods are not usually very efficient, viruses have been used in many gene therapy applications. Although efficient at actually delivering genes into target cells, there are problems associated with their use including infection of non-target tissues and dangerous immune responses.
Dr Martin Blomley, Consultant Radiologist at the Hammersmith Hospitals NHS Trust and Senior Lecturer in the Imaging Sciences Department of Imperial College London, commented:
"What we’ve found here seems a promising lead into a new, safe and effective way of delivering genes into target cells – in this case muscle tissue. The combination of microbubbles and ultrasound may offer a targeted approach to gene therapy. In addition, the microbubbles alone have some effect, and we are exploring why this is in further work.
Gene therapy holds great promise in future for curing and ultimately preventing serious diseases but is still in its infancy as a clinical tool. This promising study suggests that there may be a less invasive and more efficient, safe and accurate technique for targeting tissue, than those currently in use.
Now we’ve found a good delivery system, we need to build on the research to improve the technique and assess the possible impact it could have on diseases such as muscular dystrophy."
The technique proved to be 10 times more effective than more conventional methods.
While some of the news reports on this story are phrased in a way that suggests this is a brand new breakthru cardiovascular ultrasound microbubble gene therapy was reported in 2000.
Progress in cardiovascular gene therapy has been hampered by concerns over the safety and practicality of viral vectors and the inefficiency of current nonviral transfection techniques. We have previously reported that ultrasound exposure (USE) enhances transgene expression in vascular cells by up to 10-fold after naked DNA transfection, and enhances lipofection by up to three-fold. We report here that performing USE in the presence of microbubble echocontrast agents enhances acoustic cavitation and is associated with approximately 300-fold increments in transgene expression after naked DNA transfections.
The latest report used muscle as a target and so it is valuable for its demonstration of the potential value of the technique for muscle targets. One downside of this approach is that it is likely to deliver genes into other tissue that is near the muscles. For instance, blood vessel cells would likely receive some of the genes. Delivery of a muscle gene into blood vessels or nerves or other tissue could cause problems if that gene started being expressed in one of those cell types. Therefore its not clear that this technique will turn out to be work well in practice. Whether it does turn out to be useful might depend on the gene being delivered and the type of tissue it is being delivered to. In some cases the gene's regulatory region may prevent it from being activated in tissue that is not the desired target tissue type.
The exact mechanism of action of microbubble gene therapy is not understood.
A new trend in bubble medicine is to use the same kind of microbubbles for therapy, in which the bubbles can act as vectors for directed drug delivery and gene transfection into living cells. The permeability of cell walls for large molecules (both drugs and genes) is dramatically increased in the presence of ultrasound and microbubbles.15 The nature of the mechanism behind this phenomenon is not yet understood. Jet formation, induced by collapsing bubbles, is one of the candidates for enhancing cell-wall permeation: Electron micrographs of insonated leukemia cells show conspicuous holes in their walls.16 Jet cavitation damage and cell-wall permeation could thus be two manifestations of the same process. However, other high-energy processes besides jets are associated with the bubble collapse and could be important: Shear and pressure forces, sound waves, and shock waves also provide significant mechanical interactions between bubble and cell.
At this point in time a diagnosis of glioma brain tumor is pretty much a death sentence. But these amazing experiments with genetically engineered neural stem cells may provide a highly precise way to kill glioblastoma cancer cells.
LOS ANGELES -- Researchers at Cedars-Sinai Medical Center's Maxine Dunitz Neurosurgical Institute in Los Angeles have combined a special protein that targets cancer cells with neural stem cells (NSC) to track and attack malignant brain tumor cells. Results of their study appear in the Dec. 15 issue of Cancer Research.
Glioblastoma multiforme, or gliomas, are a particularly deadly type of brain tumor. They are highly invasive with poorly defined borders that intermingle with healthy brain tissue, making them nearly impossible to remove surgically without catastrophic consequences. Furthermore, cells separate from the main tumor and migrate to form satellites that escape treatment and often lead to recurrence.
Cedars-Sinai researchers recently published results of a study showing that neural stem cells have the ability to track glioma cells as they migrate. By engineering neural stem cells to secrete interleukin 12, they were able to elicit a local immune response that attacked cancer cells at the tumor site and in the satellites.
The current study used genetically engineered neural stem cells – cells that have the potential to differentiate into any of several types of cells of the central nervous system – to deliver a protein that is known for its cancer-fighting properties: tumor necrosis factor related apoptosis inducing ligand, or TRAIL. TRAIL has been shown to cause apoptosis, or cell death, in several types of cancers without causing toxicity to normal cells.
In vitro studies demonstrated that unmodified TRAIL cells quickly attacked human glioblastoma cells, with nearly all of the tumor cells being killed within 24 hours. TRAIL-secreting neural stem cells also resulted in significant cancer cell death, and the genetically engineered stem cells maintained their viability, strongly expressing TRAIL for as long as 10 days.
Similar results were found in vivo when human glioblastoma cells in mice were treated with TRAIL-secreting NSC and controls. A week after treatment, strong secretion of TRAIL was visible in the main tumor mass and in disseminating tumor pockets and satellites, indicating that the engineered cells were actively tracking tumor cells. The tumors treated with NSC-TRAIL had also decreased significantly in size, compared with the controls. Furthermore, while the treatment was dramatically effective in killing glioma cells, it was not toxic to normal brain tissue.
Note that the scientists were able to test human neural stem cells in a mouse model of the disease. The ability of human stem cells to live in mice allows the more rapid development of stem cell therapies for humans.
Two new results reported on transplanting cells into damaged hearts. The first with humans increased the pumping capacity of hearts:
Researchers conducted the multi-center trial, overseen by the U.S. Food and Drug Administration, in patients who had suffered heart attacks or heart failure and whose hearts had reduced pumping ability evidenced by left-ventricular ejection fraction (EF) less than 30 percent. EF measures the quantity of blood pumped from the heart with each beat. A healthy heart pumps out a little more than half the heart's volume of blood with each beat for an EF of 55 percent or higher.
Eleven patients were undergoing coronary artery bypass surgery (CABG) and five were having a left ventricular assist device (LVAD) implanted. An LVAD helps a failing heart until a donor heart becomes available for transplant.
The patients' myoblasts cells (immature cells that become muscle cells) were extracted from thigh muscle. Large quantities of the cells were grown in the laboratory for three to four weeks using a controlled cell expansion manufacturing process. During the surgery, one to 30 direct injections – containing 10 million cells each – were made into the damaged area of the hearts. The dosages ranged from 10 million to 300 million cells.
"We found that the transplanted myoblasts survived and thrived in patients. Areas damaged by heart attack and cardiovascular disease showed evidence of repair and viability," Dib says.
No significant adverse reactions were found related to the cell transplant procedure in either group of patients in follow-up testing nine months later.
There was one death due to infection of the device in the LVAD group three months after cell transplantation, and one patient in the CABG group had non-sustained ventricular tachycardia – a fast heart rate that starts in the lower chambers (ventricles).
While the trial was not designed to evaluate the effect of cell transplant on cardiac function, Dib calls the results extremely encouraging. Examining the heart by echocardiogram, magnetic resonance imaging (MRI), and positron emission tomography (PET scan) showed evidence of scar tissue regeneration in the area of the graft, which indicates repair.
EF rates improved, on average, from 22.7 percent to 35.8 percent – a 58 percent increase – after 12 weeks.
CHICAGO, Nov. 17 – Preliminary findings of a study in rats suggests that a person's own cells might one day replace artificial pacemakers, researchers reported today at the American Heart Association's Scientific Sessions 2002.
Studies conducted at Children's Hospital Boston tested the ability of immature skeletal muscle cells to interconnect with heart cells and spread the electrical impulses that keep the heart beating properly.
"The cells have survived in rats for more than a year and they appear to have made connections with cardiac cells," says Douglas B. Cowan, Ph.D., a cell biologist who led the study. "The electrical pathway developed within 10 weeks of implantation.
"Ultimately – maybe a decade down the road – we may be able to use such cell-based technologies in humans to free them from cardiac pacemaker devices," says Cowan, also an assistant professor of anesthesia at Harvard University Medical School in Boston.
Heart contraction starts with an electrical signal that begins in the atrium, a tiny area of the heart's upper-right chamber. The signal then moves to the other chambers. Damage to the electrical pathway between the atrium and ventricles (the lower chambers) can result in complete heart block, a potentially fatal condition that can only be treated by implanting a cardiac pacemaker.
"We have gathered preliminary evidence that immature skeletal muscle cells can establish a pathway to transmit electrical signals from the heart's upper right chamber to its lower right chamber," he says.
In one sense these treatments were fairly low tech (though heart surgey isn't exactly low tech). It wasn't necessary to apply complex chemical treatments to embryonic stem cells in order to get them to differentiate into heart cells. They used myoblasts which are essentially muscle stem cells. Also, their method of growing them up may be fairly sophisticated. It seems logical to expect that in the longer run younger sources of myoblast cells will eventually be used because they will be more efficient and last longer.
Update: A third result has blood vessels being grown from human skin cells:
CHICAGO, Nov. 17 – Researchers have built mechanically sound blood vessels out of tissue from human skin cells, according to a study reported today at the American Heart Association's Scientific Sessions 2002. The technique involves tissue engineering, an emerging science that takes cells from the body, manipulates them in the laboratory to create functional tissue, and puts the new tissue back into the patient.
The goal is to produce healthy, functioning blood vessels built exclusively from a person's own cells, so the body's immune system won't reject the new tissue. Such vessels would be important in heart and leg bypass operations and for vessels called arteriovenous shunts used for dialysis patients.
The scientists reported that tissue-engineered blood vessels didn't burst or develop blood clots in laboratory tests and short-term animal experiments.
"The study's most important findings were: First, the technology works from a commercial perspective, meaning we can build mechanically sound vessels for a wide array of patients using the exact same protocol," says Todd McAllister, Ph.D., president and chief executive officer of Cytograft Tissue Engineering in Novato, Calif., which developed the vessel-building technique.
"Second, we demonstrated that thrombogenesis (the formation of blood clots) does not appear to be a problem in the short term – up to 14 days. Short-term blood clots are the biggest challenge facing most synthetic materials, whether they are used for blood vessels, new heart valves, or other vascular prostheses. We expect to begin this research in humans within 18 months."
Update II: A fourth result show bone marrow transplantation improving arteries in the legs and feet:
“This is the first multicenter and double-blind clinical study to prove the clinical efficacy of growing new blood vessels (angiogenesis) using bone marrow cell transplantation,” says the study’s lead author Hiroya Masaki M.D., Ph.D. He hopes that transplanting bone marrow cells will establish a new therapy for peripheral artery disease (PAD).
PAD is a condition similar to coronary artery disease in which fatty deposits build up along artery walls and reduce blood circulation, mainly in arteries leading to the legs and feet. In its early stages, a common symptom is cramping or fatigue in the legs and buttocks during activity. PAD causes severe pain, ulcers and sores. In its later stages, it can lead to gangrene or a dangerous lack of blood flow, called critical limb ischemia, which can be treated by revascularization (such as angioplasty) or amputation.
Bone marrow cells are promising for this type of therapy because they have the natural ability to supply endothelial progenitor cells, says Masaki, an associate professor in the department of laboratory medicine and clinical sciences at Kansai Medical University in Osaka, Japan. Endothelial progenitor cells can develop into endothelial cells, which, in turn, can form new blood vessels.
The researchers randomly implanted either a person’s own bone marrow mononuclear cells or saline (a placebo) into the calf muscles of 45 PAD patients. Twenty patients had bilateral ischemia (both legs) and 25 had unilateral ischemia (one leg). There was a “striking” increase in new capillary formation in the legs of patients who received bone marrow mononuclear cell transplants. Patients injected with saline showed much smaller increases in collateral perfusion.
Researchers found that CD34-cells, which can develop into endothelial progenitor cells, expressed basic fibroblast growth factor, vascular endothelial growth factor and angiopoietin-1. These vascular growth factors play key roles in angiogenesis.
“Endothelial progenitor cells have vascular growth factors inside the cells,” Masaki says. “This is very advantageous for angiogenesis. By implanting the bone marrow mononuclear cells, we deliver endothelial progenitor cells and vascular growth factors at the same time.”
In limbs that received the bone marrow cells, researchers noted an increase in ankle-brachial pressure index (ABI) in 31 of 45 patients. Baseline ABI was 0.35. Four weeks after implantation it was 0.42, and at 24 weeks it was 0.46. The ankle-brachial index test measures blood pressure at the ankle and in the arm and divides the two to help predict the severity of PAD. A normal resting ABI is 0.30 – 0.91. Patients with leg pain typically have ABI indexes ranging from 0.41 – 0.90, and those with critical leg ischemia have indexes of 0.4 or less.
Researchers also noted newly visible collateral vessels in 27 limbs. Pain occurring at rest in the ischemic limbs diminished significantly in 39 of 45 patients, and the amount of time they could walk on a treadmill without pain was significantly improved (from 1.3 minutes at baseline to 3.6 at week four and 3.7 at week 24). Participants’ ischemic ulcers or gangrenes were healed in 21 of 28 limbs.
Update III: A fifth result shows bone marrow transplantation improves the function of damaged hearts:
The study by British researchers adds to mounting evidence that muscle-generating cells in bone marrow can rejuvenate hearts deadened by infarctions, or loss of blood to the tissue. Previously, scientists had considered that damage irreversible.
"It has been the belief in general that you are born with a fixed number of [heart muscle cells], and that when they die they die forever," says Dr. Manuel Galinańes, a heart surgeon at the University of Leicester and leader of the research effort. "This has been challenged."
The compound delta opioid peptide is used in squirrels to induce stroke but it also is made in human nerves in response to stroke and larger doses administered therapeutically may reduce stroke damange and provide protection against other neural disorders:
In an animal model for stroke, delta opioid peptide reduced by as much as 75 percent the damage to the brain’s striatum, the deeper region of the brain and a major target for strokes, according to Dr. Cesario V. Borlongan, neuroscientist.
In fact, evidence suggests that the compound, which puts cells in a temporary state of suspended animation, may help protect brain cells from the ravages of Parkinson’s disease as well.
“When the animals were introduced to an experimental stroke, then injected with delta opioid peptide, we could see a reduction in the damage done by stroke; brain damage is reduced and the neurological deficits associated with stroke are definitely reduced,” Dr. Borlongan said.
This compound may even be useful in slowing the aging process and protecting ogans while waiting to transplant them:
The researcher believes this cell hibernation may have other roles as well, including slowing the aging process. Its potential for helping donated livers, hearts and kidneys remain viable longer until they are transplanted already is being explored by others in clinical trials.
I'm reproducing this press release in full here because it describes such an incredibly promising technique for treating a large assortment of diseases. The ability to target drugs to activate in only the cell types that express a particular gene would allow great specificity of delivery.
Tailor-made Cancer Drugs: Wave of the Future? Washington University chemist offers radical new strategy in fight against cancer.
[St. Louis, MO., 10-27-02]
By Carolyn Jones Otten
Today, even the best cancer treatments kill about as many healthy cells as they do cancer cells but John-Stephen A. Taylor, Ph.D., professor of chemistry at Washington University in St. Louis, has a plan to improve that ratio. Over the last several years, Taylor has begun to lay the conceptual and experimental groundwork for a radical new strategy for chemotherapy -- one that turns existing drugs into medicinal "smart bombs," if you will.
All DNA is formed of three basic components: a phosphate and a sugar, which combine to form the sides of the double helix "ladder," and a base that forms the ladder's "rungs." All variances in DNA, including cancerous mutations, are the result of unique sequencing of the four types of bases, denoted A, G, C and T.
Taylor's approach, described as "nucleic acid-triggered catalytic drug release," is essentially a sophisticated drug releasing system, one that is able to recognize and use cancerous sequences as triggering mechanisms for the very drugs that fight them.
"The beauty of this system is that it could use already-approved FDA drugs," Taylor explained. "So all I have to worry about is getting FDA approval on the general releasing mechanism, and then I can incorporate whatever anticancer drugs are currently on the market."
Taylor discussed his work at the 40th annual New Horizons in Science Briefing, a function of the Council for the Advancement of Science Writing. He spoke Oct. 27, 2002 at Washington University in St. Louis, which hosted the event.
Guiding drugs to their 'parking spot'
In nucleic acids, Nature has already determined the rules of base pairing -- A binds with T and G pairs with C -- a system called "Watson-Crick base-pairing," named for the discoverers of the double helix. Recent advances in biotechnology have given doctors the ability to profile a patient's genetic information, taken during a biopsy, using something called a DNA chip, which can identify unique or uniquely overexpressed messenger RNA (mRNA). Messenger RNA is a single-stranded RNA molecule that encodes information to make a protein, using the same bases as DNA except that U replaces T. Taylor's idea is to employ this information as a genetic roadmap, guiding drug components to where they should "park" amongst the millions of base pair "spaces."
Taylor's system is built on three components: a "prodrug," or a dormant form of a drug; a catalyst that activates the prodrug; and a nucleic acid triggering sequence, designed to match and interlock with a unique or uniquely overexpressed strand of RNA in cancerous cells. The RNA binding drug components will be fashioned out of Peptide Nucleic Acid (PNA), which is identical to DNA, but replaces the sugar backbone with a "peptide" or protein backbone. The benefit is that a single strand of RNA actually binds tighter to a strand of PNA than it does to itself.
So, the prodrug and the catalytic components each contain a PNA strand that is complementary to the cancer cell's mRNA, allowing them to bind right next to one another in the cancer cell. This close proximity enables a chemical reaction to occur between them, resulting in the release of a cytotoxic drug which kills the cancer cell. Although the medication might encounter healthy cells in its travels, it would not harm them because the RNA triggering sequence would not be present, or else present in a much lower amount, and the drug could not be released.
This new "rational" design doesn't stop there -- it could be the answer to all sorts of viral diseases such as AIDS, hepatitis and herpes, and could even help guard against new biologically engineered viruses that we haven't yet imagined.
"Here's my vision of the future," Taylor said. "You go to a doctor's office and take a biopsy, which is then run through a DNA chip analysis machine allowing the appropriated triggering sequence to be identified. This information is then passed to an automated synthesis machine and, iIdeally, the catalytic and prodrug components can be synthesized and administered to you within hours."
In related work, Taylor said he will be using overexpressed RNA sequences to help target drugs in research with Washington University colleague Karen Wooley, Ph.D., associate professor of chemistry, and other collaborators. The group hopes to splice Taylor's RNA-docking molecules to Wooley's new breed of nanoparticles for on-the-mark, stay-put delivery of diagnostic and disease-fighting agents.
Contact: Gerry Everding, Office of Public Affairs, Washington University in St. Louis, (314) 935-6375; email@example.com
You can find Dr. Taylor's web page here.
It is not clear from this report what technique they used to shut down the Huntington's gene. If they genetically engineered the mice to make the gene able to be shut down by pharmaceutical means then this result is only useful for studying the disease. But if they developed a drug that could shut down the regular regulatory region for this gene then the technique might be closer to a treatment usable on humans. If anyone knows exactly what they did do tell. Still, the fact that the toxic protein will clear out if the cell can be made to stop making it is good news for Huntington's patients:
Researchers have devised a clever genetic technique in mice that can regulate the production of the abnormal protein that causes Huntington's disease.
Ai Yamamoto, a researcher at Memorial Sloan-Kettering Cancer Center, created an animal model that exhibits all the signs of the lethal disease: brain damage and impaired movement. When the mutant gene is shut off, toxic protein deposits clear out and the animal improves substantially. Yamamoto presented her findings last week at the American Neurological Association's annual meeting in Manhattan.
Science Daily's published press release from Thomas Jefferson University has the most detail of the reports I've seen so far.
According to Dr. Oshinsky and Jia Luo, M.D., research associate at Jefferson Medical College of Thomas Jefferson University, in Parkinson's, a portion of the brain called the subthalamic nucleus is overactive. These cells produce glutamate, an excitatory neurotransmitter, or chemical message carrier, into another region called the substantia nigra, which is important for the coordination of movement and where the brain chemical dopamine is made. Parkinson's is caused by the deterioration of dopamine-producing nerve cells.
The researchers - including scientists from Jefferson, the University of Auckland, New Zealand, and Cornell University - took their cues from work with deep brain stimulation, where brain cells in the subthalamic nucleus are stimulated at a high frequency as a treatment for late-stage Parkinson's. This treatment prevents overactivity in the substantia nigra.
The team, led by Matthew During, M.D., formerly of Jefferson Medical College of Thomas Jefferson University and now at the University of Auckland, decided that instead of turning off the neurons in the subthalamic nucleus, they would attempt to change the neurons from excitatory to inhibitory, which would then contain the inhibitory chemical messenger GABA.
The team used an adeno-associated virus to carry the gene for an enzyme, glutamic acid decarboxylase (GAD), into brain cells in rats that were made Parkinsonian. They saw a dramatic difference in the behavior and physiology of the Parkinsonian rats treated with the GAD-carrying virus compared to the Parkinsonian rats that did not receive the treatment.
Three weeks after the gene transfer, Dr. Luo made Parkinson's lesions on one side of the brains of rats that had the gene therapy. The researchers then performed various behavioral tests to see if the gene therapy could protect against the development of classic Parkinson's symptoms. One test showed that nearly 70 percent of the animals with Parkinson's lesions and the GAD gene therapy had no Parkinson's symptoms when they received chemicals that mimicked dopamine in the brain. Normally, animals with Parkinson's are hypersensitive to dopamine, and actually respond to it by running around in circles over and over. The test result was a "very strong behavioral measure showing this is a good treatment for Parkinson's," Dr. Oshinsky says.
If anyone wants to find Jefferson Medical College of Philadelphia PA then click here for contact information. Though possibly the Department of Neurology might be what you are looking for. Jefferson's Farber Institute for Neurosciences looks like it might be the place for Parkinson's treatment.
The first human clinical trial of a gene therapy treatment for Parkinson's disease is set to begin in the US, following successful results in animals.
Some day in the future everyone will have perfect eyesight. Some Johns Hopkins scientists have just moved us closer to that day:
Surgeons at Johns Hopkins' Wilmer Eye Institute are now offering conductive keratoplasty, or CK, to correct low-level farsightedness in selected patients over age 40.
The procedure, approved in April by the U.S. Food and Drug Administration, is the first non-laser treatment for hyperopia, a condition in which people can see objects far away but have trouble focusing on those nearby. It is an outpatient surgery performed under local anesthesia in just a few minutes.
Unlike laser treatments, which use light waves as an energy source, CK uses radiofrequency waves, a form of electromagnetic energy, to re-shape the peripheral cornea. The energy is similar in some respects to the microwaves that power CB radios and cell phones.
CK employs a pen-shaped instrument with a tip as thin as a human hair that releases the radiofrequency energy. The tip is applied in a circular pattern on the outer layer of the front of the eyeball to shrink small areas of tissue. The result is a constrictive band of tissue, similar to a tightened belt, that increases the overall curvature of the cornea.
"Nearly 95 percent of patients with low to moderate ranges of farsightedness achieve normal or near-normal vision after the procedure," says Terrence P. O'Brien, M.D., medical director of the Wilmer Laser Vision Center in Lutherville, Md.