Leslie Gordon's son Sam was 22 months old when he was diagnosed with Hutchinson-Gilford Progeria syndrome, a devastating disease in which children age rapidly and usually die between their 7th and 20th birthdays. Gordon, an MD/PhD, and her MD husband, Scott Berns, discovered an astonishing void of information on the disease, which is so rare that it affects only 1 in 4-8 million live births. "There was nothing," says Gordon. "There were no more than 100 publications in total throughout history. There had never been any NIH funding, there were three to four scientists in the world studying it, and there was no active research program."

For lack of existing organizations, they founded their own, the Progeria Research Foundation. They created a cell and tissue bank, and raised enough money to give out fifteen $100,000 research grants to date. A...

It helped to have powerful allies. As a former White House Fellow, Berns had met Francis Collins, the director of the National Human Genome Research Institute. Collins had been deeply affected by meeting and treating a progeria patient named Meg Casey years earlier at Yale. "I thought this would be a great research project, but there was no real approach one could take in a disease that was so rare," Collins says. "So it went on the back burner for about 17 years."

Collins became an enthusiastic supporter and advisor. One of his postdocs, Maria Eriksson, started working on the disease, and in 2003, the team, including Gordon, published evidence that defects in the gene for lamin A were responsible for Hutchinson-Gilford progeria (M. Eriksson et al., Nature, 423:293-8, 2003). The defects create a cryptic splice site so that the resulting lamin A protein lacks 50 amino acids, creating a molecule Gordon calls progerin. Without these amino acids, a farnesyl group that attaches lamin A to the inner nuclear membrane is never removed, and the lamin A "binds to the inner nuclear membrane and won't let go," says Gordon. Such binding creates characteristic "blebs" in the membrane of affected cells. "The stars have aligned," Gordon says. The gene defect provided more than they could have imagined.

Farnesyl transferase inhibitors (FTIs), it so happened, had already been in testing for various cancers. Several studies have now shown that such inhibitors reverse the effects of the progeria lamin A mutation in vitro; in vivo demonstrations appear close at hand. Two mouse models of progeria now exist: one that has a mutation in a lamin A processing enzyme (L.G. Fong et al., Science, Feb. 16, 2006, e-pub ahead of print), and one that the Collins lab created with the lamin A defect they discovered (R. Varga et al., PNAS, Feb. 21, 2006, e-pub ahead of print). FTIs have reversed some of the progeria-like pathology in the Fong model. Collins' lab began testing the inhibitors on its new mouse model a few months ago and is waiting to see if the drug will prevent the cardiovascular symptoms of the disease. If those tests are successful, Collins is hopeful about getting human trials started soon. "We still don't know whether this treatment will be beneficial in these kids," says Collins. "We won't know for at least a year. It's hard to tell in a disease that is slowly progressive."

Collins is still moved by the work. A few years ago, discovering an unusual lamin A mutation in an archived skin biopsy from an unusually mild case, he was surprised to find his own initials at the end of the report. The biopsy was from Meg, who died of the disease at age 28. Sam, now nine, has already witnessed great strides in understanding for his disease, but he's mostly just a happy third-grader with lots of friends who love him just the way he is. "Francis told me not too long ago that there have been more than 200 gene defects responsible for disease processes found in the last several years and none of them, as far as I know, have led to a treatment in the way that this one may," says Gordon.

"They have inspired a lot of researchers to take an interest in a disease that had been largely ignored because of its rarity and the absence of any really exciting research ideas," says Collins of the foundation. "The number of papers being published now on progeria is just dizzying, especially when you consider that before 2003 almost nothing was going on." It's "an example of the kind of thing we want to see happen for many other rare diseases," he adds. "This is the future we've been dreaming of."

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