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GENETICS
Liver Cirrhosis in Mice Inhibited by Telomerase Gene TherapyProcedure May Prolong Survival in Human Cirrhosis Patients Telomere loss plays a major role in the development of cirrhosis of the liver, according to a study in the Feb. 18 Science by researchers at the Dana–Farber Cancer Institute. Telomeres, long stretches of repeating DNA sequences at the ends of eukaryotic chromosomes, are thought to protect DNA from damage. Since they shorten each time DNA replicates—each time a cell divides—and are eventually depleted, they may play a key role in cellular senescence. Indeed, many scientists now believe that telomeres are the molecular clock of aging. A research group led by Ronald DePinho, HMS professor of medicine (genetics), hypothesized that telomere loss is the reason that liver cells stop dividing and succumb to damage in cirrhosis, which affects hundreds of millions of people worldwide. Although the liver has a powerful capacity to regenerate, at some point hepatocytes stop dividing and die, signaling the conversion of normal liver to thick fibrous tissue. Cirrhosis results in death when too few cells are left to cope with the liver's vast biochemical functions.
Above are liver sections of mice with normal-length or shortened telomeres six months after repeated carbon tetrachloride treatment. Marked lipid accumulation (cavity-like appearance) and fibrosis (red stain) are evident in livers of mice with short telomeres. To prove their hypothesis, DePinho; K. Lenhard Rudolph, HMS research associate in medicine; Sandy Chang, HMS clinical fellow in pathology; Melissa Millard, research technician; and Nicole Schreiber-Agus from the Albert Einstein College of Medicine induced liver damage in mice born with short telomeres. After six months of repeated administration of carbon tetrachloride, a powerful liver toxin, the mice developed cirrhosis, demonstrated by pronounced lipid accumulation and fibrotic scarring (see figure). Mice with normal telomere lengths did not develop cirrhosis. Livers of telomere-deficient mice were also unable to regrow normally after surgical removal of two-thirds of the organ. The researchers next tested whether delivery of a gene—telomerase RNA (mTR)—to the livers of telomere-deficient mice could prevent cirrhosis after carbon tetrachloride administration. The mTR gene encodes an essential component of telomerase, the enzyme that makes telomeres. Delivery of mTR alleviated cirrhotic pathology and improved liver function. "This study offers the first formal proof that the onset of cirrhosis is related to shortening of telomeres," DePinho says. He believes telomerase gene therapy may turn out to be useful for a wide spectrum of chronic diseases in which regenerative capacity is crucial. For example, in AIDS, telomerase delivery to bone marrow cells might prolong the replacement of immune cells destroyed by HIV. It may also help restore regenerative capacity to the bone marrow in myeloproliferative diseases such as chronic myelogenous leukemia. In their paper, the authors address the likely concern of many people that telomerase gene therapy may pose a cancer risk. It is known that cancer cells have learned to switch on telomerase. They say, to the contrary, that telomerase might actually inhibit cancer by preventing the inevitable genomic instability that results from telomere loss. Indeed, they have observed an increased cancer incidence among aging telomere-deficient mice. Nevertheless, the authors acknowledge that such possible adverse effects of telomerase reactivation have to be considered. The researchers believe that patients with end-stage cirrhosis might be ideal candidates for telo-merase therapy. They say that telo-merase-mediated improvement would prolong their survival while they await liver donors, and that the eventual removal of the livers should minimize potential cancer risk. —Lorene Leiter |
