Papers on these two experimental approaches both appear in the February 18th issue of Science.
In one of the studies, a multicenter team of researchers led by Dr. Naoya Kobayashi, of Okayama University Medical School in Japan, isolated human hepatocytes in vitro and transfected the cells with an oncogene that immortalized the cells, causing them to double every 48 hours. To enable the proliferative mechanism to be turned off, the cells were concurrently transfected with a gene system that, when transiently activated, excises the immortalizing gene from the genome.
These cells were then transplanted into the spleens of rats with liver failure induced by partial hepatectomy. The researchers report that "90% of hepatectomized rats having undergone transplantation...showed significant improvements in all parameters" compared with control rats.
Dr. Kobayashi's co-author, Dr. Philippe Leboulch, of the Massachusetts Institute of Technology and Harvard Medical School, explained that currently, it is possible to inject normal human hepatocytes into ailing livers to help patients survive for a few days or weeks, but there is a limited availability of liver cells. The new technique of temporarily immortalizing hepatocytes has the potential to increase the supply.
"It's a temporary approach to liver failure to allow patients to live long enough" for a transplant, he said in an interview with Reuters Health. Dr. Leboulch mentioned 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.
The effect of telomerase gene delivery is the topic of the other study reported in Science. One of the investigators, Dr. Ronald A. DePinho, the American Cancer Society research professor at Harvard Medical School and Dana-Farber Cancer Center in Boston, Massachusetts, explained that knockout mice lacking the essential telomerase RNA gene develop cirrhotic symptoms.
"We now have a very good idea of what one of the seminal events of cirrhosis is telomere attrition," Dr. DePinho told Reuters Health. The researchers found that adenoviral transfer of the telomerase gene into the livers of the knockout mice resulted in the alleviation of cirrhotic pathology and improvement in liver function.
"We were able to completely block the development of cirrhosis," Dr. DePinho said. He noted that this is the "first proof of principle for telomerase therapies."
According to Dr. DePinho, there is some concern that telomerase therapy may increase the risk of cancer by encouraging cell growth. Conversely, shortened telomeres may cause genetic instability and so telomerase therapy might actually prevent cancer, he said.
Dr. DePinho noted that the potential cancer risk has to be investigated, as well as the best method for delivering telomerase, before clinical trials can begin.
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