Sep 26, 2001 (United Press International via COMTEX) -- In findings with implications for cancer and aging, British researchers have discovered a partial loss of function of an enzyme once hailed as an elixir of youth leads to a rare, incurable disorder that can set off a progressive deterioration of bone marrow.

The inherited disease, called dyskeratosis -- which means and results in abnormal formation of skin and nails -- congenita, might be a good target for gene therapy, Philip Mason of the Imperial School of Science Technology and Medicine at Hammersmith Hospital in London and colleagues said in the British journal Nature.

In their genetic study of three families, including one from Iowa, the team mapped the gene mutated in the disease and found that in individuals with the disorder, the enzyme telomerase fails to fulfill its mission of maintaining key DNA strands at the ends of chromosomes, called telomeres. In the enzyme's absence, the telomeres shrink with each cell division until they become so short, the cells stop dividing.

The observations shed new light on the role of telomerase in the human body -- which it does not play in mice -- in cancers and in aging, investigators told United Press International.

Telomerase hit the front pages in 1998 when researchers reported it allowed human cells to remain young and continue to divide indefinitely. With visions of a wide array of potential biopharmaceutical applications, including drug development, screening and toxicology testing, researchers targeted the enzyme for intense study.

Scientists also had their eye on the enzyme -- which is needed for cancer cells to divide -- as an ideal target for anti-cancer therapy, with biotechnology companies pumping millions into finding a telomerase inhibitor. Underlying the research was the distinct difference in telomerase activity in normal cells -- where its production is shut down early on, during embryo development -- and in cancer cells -- where it continues to be function vigorously.

The new findings are "very consistent with short telomeres causing chromosome rearrangements that promote cancer," said Leonard Guerente of the Massachusetts Institute of Technology in Cambridge, Mass., who co-authored an accompanying commentary.

Indeed, dyskeratosis congenita is associated with an increased cancer risk, scientists said.

"The patients get cancer, likely due to chromosomal instability brought about by abnormally shortened telomeres caused by the decreased telomerase activity," said Dr. Robert Marciniak, assistant professor of medicine and cellular and structural biology and assistant division chief of medical oncology at the University of Texas Health Science Center in San Antonio. He co-authored the News and Views article.

The study also shows how the disease exemplifies the telomerase function of expanding cell lifespan, affecting the skin, nails, bone marrow and other tissues where cells continuously divide, scientists said.

As its name implies, dyskeratosis congenita is characterized by a lace-like pattern of skin pigmentation and unusually formed nails as well as hair loss and tear duct irregularities. Symptoms can first appear in children as young as 2 or stay hidden for 30 years or longer, though in most cases the disease strikes in adolescence or early adulthood.

"Affected individuals have reduced telomerase activity and this causes the inability to maintain tissues with rapidly dividing cells. Telomerase is required for cells to divide many times," Guarente told UPI. "It has been proposed that shortening telomeres is a cause of human aging. However, this seems unlikely since the symptoms of DC do not look like normal aging."

"I think the study implies that it is likely to be more difficult to use telomerase as a 'youth elixir,'" Marciniak said. "Simply decreasing the telomerase enzyme activity doesn't cause 'accelerated aging' so simply increasing the activity would be less likely to decrease aging rates. Life and medicine is more complicated."

For example, not all tissues in the body have telomerase-producing cells, in part as a cancer preventative.

"Those tissues that don't express telomerase -- like the deep layers of the skin or the lining of blood vessels -- don't develop cancer," Marciniak pointed out. "But they do develop some of the most stereotypical changes of aging: sagging skin and vascular disease. Because of the tissue-specific pattern of regulation of telomerase expression, we don't die of sarcoma, a connective tissue cancer, when we are 5 years old, but we pay the price of sagging skin, loose joints and a host of other maladies when we past 40 or 50 years of age."

"We speculate that telomere maintenance ... is important for preventing age-related changes in tissues with lower rates of cell divisions," Marciniak added. "These tissues -- such as the dermis of the skin -- are those that are most strongly affected by 'aging.' I would suggest that since a decrease in the activity of telomerase does not cause an accelerated aging syndrome, it says that insufficient telomerase activity is not directly responsible for aging."

The research has a two-fold significance, Marciniak said.

"First, it shows that telomere maintenance -- preventing the erosion of chromosome ends -- is important in humans. The telomerase knockout mouse showed that it is not important in mice. The importance of telomere maintenance to any process had not been previously demonstrated in humans," he told UPI. "Secondly, it shows that telomerase is most important for telomere maintenance in tissues such as the epidermis and nails and bone marrow in which cell division occurs constantly."

Affecting perhaps a few thousand people worldwide, the most common form of DC is X-linked, like hemophilia, meaning most patients are male. Death results from the body's failure to replenish blood cells.

"Most patients die of bone marrow failure, called fatal anemia or complications of treatment for bone marrow failure," Marciniak said. "When they die depends on how severe their mutation was. The anemia can develop as early as 2 years and maybe as long as 30-plus years. In very mild cases of the disease, you have to wonder whether it is correctly diagnosed. Now that we know the molecular defects ... we can accurately diagnose the condition," which currently is treated primarily with bone marrow transplants.

The disease could be "a good candidate for treatment by the emerging gene transfer methodologies," Mason and team concluded.

"It's the blood problems that kill most patients at present -- not the skin and nail problems or the cirrhosis of the liver. Already, autologous (self) bone marrow transplant is being used to treat the blood problems. That is, when a patient is diagnosed, but has not yet developed the anemia, his blood 'stem cells' (progenitor cells) are collected and frozen. When he later develops the blood problems, they are re-infused," Marciniak said.

"The idea with telomerase-based gene therapy would be to put another copy of a functional telomerase gene into these cells while they are out of the body, and then re-infuse them. Autologous (self) transplants don't have all the problems with rejection that allogeniec (matched from someone else) transplants do.

He said the problem with the current therapy with autologous transplants is that the "transplanted stem cells are still diseased -- they still carry a defective copy of the telomerase gene." This might be corrected by "gene therapy."

From Healthy.net