CHAPEL HILL – Working together, scientists at the National Institutes of Health and the University of North Carolina at Chapel Hill have developed a promising new strategy for treating a form of progeria. That rare but deadly and heartbreaking genetic disease causes children to age remarkably fast and die almost always before they complete their teens.
The average lifespan of victims, who eventually resemble very old bald people or, some might say, Hollywood's conception of space aliens, is 12 years.
Along with their staffs and students, Dr. Francis S. Collins, director of the National Human Genome Research Institute, has collaborated with Drs. Channing J. Der and Adrienne D. Cox of the UNC School of Medicine in laboratory studies.
They have shown that certain anti-cancer drugs known as FTIs can block some of the complex biochemical processes that result in progeria's symptoms. The collaboration came about because the UNC scientists have been working on the drugs for more than a decade, and Collins' group has been actively investigating progeria of childhood, which also is known as Hutchinson-Gilford syndrome.
The potential treatment has not been used with patients yet but had a strong positive effect on progeria patients' cells, they said.
Respectively, Cox and Der are associate professor of radiation oncology and pharmacology and professor of pharmacology and members of UNC's Lineberger Comprehensive Cancer Center. Collins, a UNC medical graduate, attracted widespread attention in 1989 as the discoverer of the defective gene that causes cystic fibrosis, another fatal illness that afflicts children.
A report on the research appears in the Sept. 6 issue of the Proceedings of the National Academy of Sciences. Other authors of the report include M.D.-Ph.D. student Brian C. Capell of Collins' NIH laboratory; NIH staff members Drs. Michael R. Erdos, Renee Varga and Leslie B. Gordon (also medical director of the Progeria Research Foundation); doctoral student James P. Madigan of Cox's laboratory; Dr. James Fiordalisi, assistant professor of radiation oncology at UNC; and Dr. Karen N. Conneely of the University of Michigan School of Public Health.
"Fortunately, progeria is very rare, and only about one child in four million comes down with it," Der said. "It was first identified in the early 1900s. Since then only 100 or so cases have been found. Still, it is quite devastating for those children who have it and their families."
He and Cox concentrate on FTIs, or farnesyltransferase inhibitors, which block the action of the enzyme farnsyltransferase. Currently, several chemical variations are undergoing clinical trials with cancer patients.
"There's a lot of interest in FTIs now because they target an enzyme that's required for a protein called RAS to cause cancer," Der said. "The idea that these FTIs also might be useful in treating progeria came up because it turns out that the gene that is mutated in that rare illness also requires this enzyme for generating an active protein known as lamin A."
In progeria patients, he said, the process that results in the normal, mature form of lamin A doesn't work correctly because of the genetic mutation, so a damaged form of lamin A is made instead. Researchers reasoned that the anti-cancer drugs might block the enzyme and hence interfere with the mutated lamin A gene's haywire actions.
"In the paper, we describe experiments showing that the mutant form of lamin A was indeed sensitive to these drugs," Der said. "The second thing we found was that some of the aberrant biology that this mutant protein causes can be stopped when we treat the cells with the inhibitors."
Because the drugs already are undergoing clinical trials and much is known about their action and safety, scientists have a significant head start in getting the possible treatment to patients, Cox said.
"We are very excited about the possibility that a drug class whose actions we have been working so hard to understand in cancer might soon be useful for this devastating 'orphan disease,'" she said. "Progeria is clearly an illness that would otherwise get no attention from pharmaceutical companies due to the tiny numbers of children afflicted."
The next step will be to test the enzyme inhibitors in mouse models of the disease which already have been made, Cox said. If those experiments succeed, then scientists could start clinical trials with patients.
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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