Gene Therapy May Help Ailing Livers

NEW YORK, Feb 17 (Reuters Health) -- Two types of gene therapy, which are both still in the experimental stages, eventually may help treat severe liver disease, at least until a donor liver becomes available for transplantation.

In one of two studies published in the February 18, 2000 issue of the journal Science, researchers report that cirrhosis, which causes the liver to become scarred and can cause liver failure, may result in part from irregularities in cell structures called telomeres. Strands of the genetic material DNA found at the ends of chromosomes, telomeres regulate the number of times a cell can divide. Over time, telomeres gradually shorten. Once they reach a certain length, they stop telling cells to divide to form new cells.

In an interview with Reuters Health, one of the researchers said that shortened telomeres appear to increase the risk of developing cirrhosis, in mice at least. In the study, mice that were genetically altered to lack telomerase, the enzyme that produces telomeres, developed signs of cirrhosis, according to Dr. Ronald A. DePinho, the American Cancer Society research professor at Harvard Medical School and Dana-Farber Cancer Center in Boston, Massachusetts.

"We now have a very good idea of what one of the seminal events of cirrhosis is -- telomere attrition," DePinho said in the interview.

But when the researchers infected the mice with a harmless virus that carried a gene to restore telomerase, symptoms of cirrhosis diminished and liver function improved.

"We were able to completely block the development of cirrhosis," DePinho said. The hope is that this treatment might be able to treat or even prevent cirrhosis in people, according to DePinho. Alcoholism, long-term infection with hepatitis B or C viruses, and certain parasites can cause cirrhosis, he noted. DePinho said he hopes that trials in people can begin within a decade, but there are still many details of the therapy that need to be worked out.

Despite the encouraging discovery, DePinho noted that there is some concern that treatment with telomerase, which encourages the growth of cells, may increase the risk of cancer. He pointed out, however, that while chromosomes with shortened telomeres can become unstable, which can increase the risk of cancer, therapy that keeps telomeres from shortening may actually prevent cancer. Still, this potential risk needs to be investigated, he said.

In the other study, researchers developed a way to grow liver cells in the laboratory that could later be transplanted into people with liver disease. Such a treatment might help people on waiting lists for a liver transplant to survive until an organ becomes available.

A research team led by Dr. Naoya Kobayashi, of Okayama University Medical School in Japan, isolated human liver cells and infected the cells with a so-called immortalizing gene that caused the cells to double every 48 hours. But placing these rapidly reproducing cells inside a person might lead to cancer, so the researchers then treated the cells with another gene that removed the immortalizing gene.

Next, these cells were placed into rats with liver failure. Ninety percent of the rats that received the transplanted cells improved significantly more than a group of rats that did not receive the cells.

If the therapy works in people, it may help many patients who are waiting for donor livers, according to the investigators.

Researcher Dr. Philippe Leboulch, of the Massachusetts Institute of Technology and Harvard Medical School told Reuters Health that, currently, it is possible to take normal human liver cells and inject them into ailing livers to help patients survive for a few days or weeks, but there is a limited number of available liver cells. The new technique of temporarily immortalizing liver cells has the potential to increase the number of available cells, according to Leboulch.

"It"s a temporary approach to liver failure to allow patients to live long enough" for a transplant, he said.

Leboulch said that the next step is to see whether telomerase therapy may help prevent liver cells from aging too quickly when they are growing in the laboratory.

SOURCES: Reuters Health, Feb. 18, 2000 AND the journal Science, Feb. 18, 2000; 287:1253-1262.


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