December 05, 2004
Gene Therapy Restores Function To Failing Rat Hearts

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.

Share |      Randall Parker, 2004 December 05 04:31 PM  Biotech Therapies

David A. Young said at December 6, 2004 8:27 AM:

I also think that 20 years from now most cancers will either be curable or controllable. If the SENS effort is more generally successful, it'll be interesting living in a world where people start thinking more and more in the long term. The changes in a culture that starts to accept the notion that death may not -- in fact -- be inevitable, should be fascinating, to say the least.

Robert Silvetz said at December 6, 2004 3:11 PM:

So how do we accelerate the trend? This nonsense about every damn cure and drug taking twenty years to bring to the fore drives me utterly bonkers!

As near as I can tell there are two out-of-the-box potential cures for diabetes skulking around the literature, at least one cytokine - BMP-7 - that can stop if not utterly reverse kidney tubulointerstitial/glomerular damage (what the f&*^% OrthoBiotech doing with it is beyond me, the patent is from 1996), at least one example of combined immunotherapy that should squash solid tumors (breast/colon) and I'm not even trying hard to find these examples.

Even if these things are not upto snuff, they are certainly not going to get there under the current FDA/NIH regime.

So how do we shake things up to accelerate breakthroughs?

Fly said at December 6, 2004 5:58 PM:

Robert: “So how do we shake things up to accelerate breakthroughs?”

Medicine specialized to a person’s genome will allow better and faster drug testing.

Better animal models. Having a good mouse model significantly speeds drug research.

Better drug targeting. Being able to precisely target specific cells, proteins, or biochemical reactions decreases unforeseen side effects.

Better tissue culture models. New drugs can be tested and observed directly on functioning brain tissue.

Better biological system and cellular computer modeling.

Randall Parker said at December 6, 2004 6:06 PM:

Robert Silvetz,

You are asking the right question!!

Here are some policy suggestions:

1) The authority of the FDA to keep drugs off the market should cease to apply for anyone who has a fatal illness. How would this work? If you can find, say, 3 doctors (and my numbers are to illustrate the point; but others could be used in actual legislation) to certify that you have an illness that places you within, say, 2 or 3 years away from absolute certain death and if existing approved drugs will not prevent your death then you should be free to take all unapproved drugs and drug sellers should be free to sell them to you.

2) Prize money should be offered to researchers who achieve various research goals. Give researchers serious financial incentives to, for example, find a way to stop the auto-immune response that causes type I diabetes. For various other illnesses and scientific mileposts set up prize money for reaching various goals along the way. Think of the X Prize philosophy applied to biomedical research.

3) There should be a legal appeals process by which people can certify their willingness to take responsibility for risking their own body with experimental treatment. This would allow people to escape the FDA approval process to get access to drugs that have been tested. For example, there is a vaccine against the Alzheimer's plaque build-up that worked for most people it was tried on. But it caused a brain inflammation in a small percentage of them. Well, if I was diagnosed with Alzheimer's I'd rather run the risk of the inflammation response (it happened in less than 5% of cases) instead of losing my mind thru a slow death. The developers abandoned attempts at approval due to the side effects. But this shows how bad the approval process has gotten. Why is the inflammation risk considered to be worse than Alzheimer's itself? This is madness.

4) Better tools: Shift more NIH money toward developing better assays and instrumentation.

5) Up the total amount of biomedical research spending. In the next fiscal year the NIH budget increase (2%) is smaller than the rate of inflation for biomedical research costs (3.5%). At the same time total medical spending is going up about 10%. So the ratio of medical costs to medical research is rising. It should be falling.

Randall Parker said at December 6, 2004 6:09 PM:

BTW, for where I got my data on medical research spending increases and inflation see my post Monoclonal Antibody Therapy Approved For Multiple Sclerosis.

Robert Silvetz said at December 6, 2004 8:30 PM:

[NOTE: Edited original comment since it included an entire copyrighted article]

For those that are interested, one cure for diabetes is on its way in case you missed the news :

Massachusetts researchers say they have cured type 1 diabetes in mice.

And the technique they used -- injecting spleen cells that remarkably turned themselves into insulin-producing cells -- holds great promise for people with the disease. However, the scientists say, a lack of funding for the necessary human clinical trials is hampering their work.

The researchers, led by Dr. Denise L. Faustman, director of Massachusetts General Hospital's Immunobiology Laboratory, are reporting in the Nov. 14 issue of Science that their technique seems applicable to other autoimmune conditions, in which the body's immune system attacks its own tissue.

"We must get 500 calls a month from people who want to be in clinical trials," Faustman says. "The enthusiasm of the patient population is impressive."

"There is a huge amount of momentum required that people don't appreciate in moving from raising $1 million dollars a year to raising $20 million a year to get human trials started," she adds.

The animal studies have been financed primarily by the Iacocca Foundation, set up by automotive legend Lee Iacocca to support diabetes research after his wife, Mary, died of complications of the disease. But "they don't have the resources to scale up to human clinical trials," Faustman says.

Randall Parker said at December 7, 2004 12:11 AM:


Your article was from 2003. But I found another article from 2001 with an earlier report from the same lab that, yes, Tumor Necrosis Factor Alpha does appear to stop type I diabetes when combined with donor islet cells.

BOSTON — June 27, 2001 — Researchers at Massachusetts General Hospital (MGH) have shown that an unexpectedly simple treatment cures type 1 diabetes in mice. Published in the July 1 Journal of Clinical Investigation, the findings are distinct from the current theories on how to treat the disease.


For the past five years, Faustman and her team have been closely examining the immune cells of diabetic mice and humans. They came across two key findings: the immune cells died when they were exposed to the naturally occurring drug, TNF-alpha, and many of the immune cells were unable to present self-peptides – a process crucial for preventing the development of autoimmune reactions.

Because of these two findings, Faustman and her team designed a two-pronged treatment strategy. First, they triggered the expression of TNF-alpha in the mice in an attempt to destroy the immune cells that had gone awry. This approach had never been used for the treatment of type 1 diabetes. On the contrary, TNF-alpha antagonists have been prescribed, an intervention that never permanently reverses or cures the disease. Antagonists of TNF-alpha are often used in the clinic as a general treatment for suppressing inflammation. "According to our findings, future efforts for diabetes treatment should look at using TNF agonists instead of antagonists," says Faustman.

So how hard is it to get donor islet cells? Well, I posted on Faustman's work a year ago and it may be that just a protein from the donor islet cells is needed along with the TNF-Alphat to retrain the immune system not to attack islet cells.

It might be possible to try Faustman's approach. She used BCG to stimulate TNF-Alpha production.

She also had to stop the attack that was under way in the pancreas. That required killing the white cells that were doing the attacking. Her solution was to give an off-patent drug, BCG, that is inexpensive, $11 a vial, and approved for use as an immune system stimulant. It elicits the release of an immune system hormone, tumor necrosis factor, that kills activated white cells.

After Dr. Faustman gave the mice the two types of treatment, the attack on the islets stopped.

Then, to her astonishment, something else happened: the islet cells grew back, a development that went against everything known by scientists.

rsilvetz said at December 7, 2004 10:42 AM:

So, in essence, they have been kicking around a potential cure now for three years and never tried it in a human?


Rosie said at March 31, 2005 8:48 PM:

If anyone is interested in setting up an organization for persons with auto-immune disorders such as diabetes, Kidney, or MS disease please write.
I would like to organize and picket the FDA office to fast tracking diabetes, MS, or kidney disease medications. Some of these medication are known to be safe, for example, BMP-7 is already being used to treat fractures in humans....

Please write back.

Rosie said at March 31, 2005 8:48 PM:

If anyone is interested in setting up an organization for persons with auto-immune disorders such as diabetes, Kidney, or MS disease please write.
I would like to organize and picket the FDA office to fast tracking diabetes, MS, or kidney disease medications. Some of these medication are known to be safe, for example, BMP-7 is already being used to treat fractures in humans....

Please write back.

Rosie said at March 31, 2005 8:49 PM:

If anyone is interested in setting up an organization for persons with auto-immune disorders such as diabetes, Kidney, or MS disease please write.
I would like to organize and picket the FDA office to fast tracking diabetes, MS, or kidney disease medications. Some of these medication are known to be safe, for example, BMP-7 is already being used to treat fractures in humans....

Please write back.

Vassili said at June 26, 2005 4:02 AM:

Rosie, great plan. I am a chronic kidney disease patient on dialysis. I have heard of BMP-7 and I have written to OrthBioTech but so far they haven't answered. Since BMP-7 has already been approved for bone protection I don't see why we can't rush through the clinical trials and offer this treatment everywhere as soon as possible.

Thanks for keeping me posted.

Christina said at July 10, 2005 1:58 PM:

Rosie and Vasili,
Let's do this. I just don't know where to go from here. I also have written ortho biotech only to receive very evasive responses.

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