Embargoed for Release
February 17, 2000
2 p.m. Eastern Time
Contact: Todd Ringler
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Gene injections can prevent development of cirrhosis in mice, study finds
Study points to potential new treatment for patients with the disease
BOSTON - The long-sought trigger for cirrhosis of the liver - the world's seventh leading cause of death by disease - may be the erosion of tiny, repetitive DNA strands called telomeres that cover the tips of chromosomes and limit the number of times cells may divide, according to a new study by researchers at Dana-Farber Cancer Institute.
The study, published in the Feb. 18 issue of Science, raises the possibility that cirrhosis and other diseases of repeated cell death and regrowth can one day be treated or prevented by delivery of genes able to rebuild lost telomeres, the authors say.
"This study offers the first formal proof that the onset of cirrhosis is related to shortening of telomeres," says the study's senior author, Ron DePinho, M.D., of Dana-Farber and Harvard Medical School. "A great deal of work still needs to be done to understand the link between telomere-shortening and this dread disease in people, but our model system provides a framework for such studies, a framework that will facilitate the development of an entirely novel therapeutic approach. Essentially, our study is the first proof-of-principal that telomerase therapy may be useful for a wide spectrum of chronic diseases, including cirrhosis."
Cirrhosis is the last stage of a years- or decades-long process in which liver cells, called hepatocytes, undergo repeated bouts of damage and destruction - usually as a result of alcoholism, infection with the hepatitis B or C virus, or parasitic infection. Such damage does not immediately result in disease because hepatocytes have the ability to regenerate, replacing injured cells with new ones.
Eventually, though - scientists have not known why - hepatocytes lose their remarkable recuperative powers. Instead of regenerating in the face of destruction, they stop growing and dividing. Their place is taken by tough, fibrous scar tissue, impeding the liver's function.
As cirrhosis sets in, the liver's ability to filter poisons from the blood declines sharply. The result can be health problems including edema (massive fluid buildup), an inability to fight infections, heart problems, cognitive problems, among other disorders.
Scientists have long sought to understand why hepatocytes eventually fail to regenerate. There were clues that the answer lay in the cells' telomeres.
"It has been theorized the telomere-shortening is responsible for the decline of hepatocyte regenerative potential that sets the stage for cirrhosis," says, DePinho. "The effects of alcohol or infection create so many cycles of cell damage and regeneration that the cells essentially run out of telomeres. The cells can no longer divide and, when they die, they stimulate the production of scar tissue."
Dana-Farber researchers conducted three sets of experiments to test whether there is a connection between functioning telomeres and liver cells' ability to regenerate.
In the first set of experiments, researchers administered repeated doses of carbon tetrachloride (CCl4) - a powerful toxin to liver cells - to the mice. As expected, the liver cells were damaged but regenerated themselves. After 7-14 doses, however, regeneration decreased, and fibrosis developed only in mice with short telomeres.
Next, researchers used gene therapy to re-start the telomere-building gene in the mice's liver cells. Again, the animals were given repeated doses of CCl4. This time, they did not develop classic symptoms of cirrhosis.
"This provides a clear demonstration that telomerase therapy can be applied to diseases whose main feature is the chronic damaging and regeneration of cells," DePinho says. "By reversing the course of telomere-shortening, we can, in effect, restore hepatocytes' ability to regenerate. This suggests that it may be possible not only to prevent diseases such as cirrhosis, but that people already with the disease can be successfully treated for it.
The second and third sets of experiments were variations on the first. Instead of using a chemical like CCl4 to damage liver cells, investigators used genetic techniques and surgery. The findings were consistent across all three experiments: hepatocytes with scanty telomeres were less able to regenerate than those with longer ones.
One of the concerns voiced about telomerase therapy is that, by rebuilding cells' telomeres, it may inadvertently cause them to become cancerous, as cancer cells telomeres do not shorten from one generation to the next enabling them to divide indefinitely.
Such concerns may be valid, DePinho remarks, but there's a flip side to the argument. "It's possible that if you deliver telomerase early - before the telomeres get too short - you may be able to prevent cells from becoming cancerous." That's because chromosomes with short telomeres are more likely to break and rearrange themselves in abnormal ways - resulting in a scrambling of the genetic code that can set the stage for cancer. From that standpoint, rebuilding telomeres may actually confer a protective cushion against cancer. Future studies will need to explore whether there are higher cancer rates in animals treated with telomerase therapy. DePinho notes.
And, while the results of this study are highly encouraging DePinho remarks that additional work is needed before determining whether the findings are applicable to cirrhosis in humans.
"We'll need to refine our model systems, and study other means of delivering the telomerase gene to cells, but if these studies support our work thus far, we may be on our way to an entirely new therapy for cirrhosis and similar diseases - disorders for which there currently are few effective treatments."
The team of researchers assisting Dr. DePinho included lead author, K. Lenhard Rudolph of Dana-Farber, Sandy Chang of Dana-Farber and Brigham and Women's Hospital, Melissa Millard of Dana-Farber and Nicole Shreiber-Angus of Albert Einstein College of Medicine.
Dana-Farber Cancer Institute is among the leading cancer research and treatment centers in the United States, and is the only center in New England to be both a federally-designated Comprehensive Cancer Center and Center for AIDS Research.
Visit http://www.dana-farber.net for more information.
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