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.
The Phase III trial for this therapy is currently recruiting patients.
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.
Cholesterol lowering statin drugs also reduce the damage caused by MS.
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).
Here's a technological advance which will be popular when it reaches the market.
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?
A treatment that reverses the development of type I diabetes might work in humans as well.
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?
Heart disease is a lot easier to avoid than cancer.
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 Crestor®). 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.
You can also lower your cholesterol with diet.
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"
While only done in rats so far the therapy may make dental repairs and replacements easier to do.
ANN ARBOR, Mich.---A University of Michigan research team has found that introducing a growth factor protein into a mouth wound using gene therapy helped generate bone around dental implants, according to a new paper in the February issue of the journal Molecular Therapy.
In a patient with a sizeable mouth wound, replacing a tooth takes more than simply implanting a new one---the patient also needs the bone structure to anchor the new tooth in place. Such reconstructive surgery today involves either taking a bone graft from the patient's chin or jaw, which leaves a second wound needing to heal, or using donated bone from a tissue bank, which yields unpredictable results.
William Giannobile, professor of periodontics, prevention and geriatrics, led a team at the U-M School of Dentistry that delivered the gene encoding for bone morphogenetic protein-7 (BMP-7) to large bone defects in rats in an attempt to turn on the body's own bone growth mechanisms. The study showed that animals that got the BMP-7 treatment produced nearly 50 percent more supporting bone around dental implants than those receiving the conventional treatment.
"This study represents a proof-of-concept investigation. We are encouraged about the promise of this treatment," said Giannobile, also an associate professor of biomedical engineering and director of the Michigan Center for Oral Health Research.
More work will need to be done before the approach can be tested in humans, Giannobile added. He said he optimistically would like to see initial trials begin in humans in four to seven years.
One can imagine gene therapy of this sort being used in conjunction with cell therapies being developed to grow new teeth.
"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.
Also see my previous posts "DNA Nanomachine Computers Against Cancer" and "A Couple Of Novel Cancer Therapies Reported".
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.
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.
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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.
Delivery of a gene into failing rat hearts makes them work normally again.
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.
Much more money is spent on MS treatment than is spent on MS research.
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.
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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.
This work builds on previous work Shapiro did with a simple biological computer in 2001.
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.
This follows on the heels of previous work by the same group that showed decreased bowel disorder in mice fed eggs of the helminth Schistosoma mansoni.
A German company is now going to start selling a pig worm egg preparation.
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 deat