A promising treatment for a rare childhood disorder characterized by rapid aging and death prevented and even reversed the most devastating effect of the disease in mice. Researchers report in Proceedings of the National Academy of Sciences USA that the therapy could potentially help youngsters combat life-threatening cardiovascular disease resulting from the genetic condition Hutchinson-Gilford progeria syndrome.

Progeria affects one in every four million to eight million births; there are about 50 cases currently recognized worldwide with 10 to 12 in the U.S. Common symptoms include fragile bones, hair loss, limited growth, stiff joints and wrinkling of the skin by as young as age two; about 90 percent of progeria patients die by age 13 from fatal heart attacks or strokes, according to the Mayo Foundation for Medical Education and Research. 

Researchers say that each progeria case arises randomly due to a single letter change in one gene of the child's DNA. The mutation—believed to occur in the father’s sperm before conception—results in the production of a toxic protein that attaches to and distorts the nucleus (the cell's command center containing its genetic material). Although cells normally multiply during growth and development, the misshapen nucleus cannot divide properly, ultimately damaging cells and accelerating the aging process.

Cardiovascular disease in these young patients develops as vulnerable cells lining the interior of major arteries (vessels that carry blood away from the heart) accumulate the toxic protein and die. This causes the arteries to stiffen and crack, leading to plaque buildup that blocks blood flow. Low-dose aspirin is often used to help prevent heart attacks, but some children even undergo bypass surgery or angioplasty (dilation of the arteries) to slow the disease.

Genetically engineered mice carrying the progeria mutation were used to test the effectiveness of farnesyltransferase inhibitors (FTIs) in combating progeria-related cardiovascular disease. FTIs restore the shape of the nucleus, thereby saving cells from premature destruction by preventing the toxic protein from attaching to the command hub.

Researchers found that FTIs not only prevented cardiovascular damage in young mice, but also reversed the disease in older animals treated after the onset of arterial damage. "We were amazed that [the drug] worked so well," says Francis Collins, a geneticist and former director of the National Human Genome Research Institute, who led the research team that identified the progeria gene mutation in 2003.

Although FTIs had been found to be beneficial in treating mice with progeria-related bone disease, Collins adds that "such compelling evidence of disease reversal" had not previously been observed for any aspect of progeria. This effect is particularly important when considering the life-threatening cardiovascular disease of progeria patients, as their diagnosis may come after vital arteries have been damaged.

The findings provide new hope that the FTIs currently being tested for safety and efficacy in progeria patients will help these children, says Leslie Gordon, medical director of The Progeria Research Foundation in Peaboby, Mass., whose 11-year-old son suffers from the disease. The phase II trial, which involves 28 kids from 16 countries, is the first to evaluate a therapy in humans against this disease. Current treatments for progeria are limited to high-calorie diets to prevent weight loss and physical therapy to alleviate joint stiffness.

Although Gordon warns that it is too early to draw any conclusions from the ongoing trial, she believes that researchers are "moving towards treatment that will help these kids' lives." Looking ahead, Gordon stresses that researchers will continue to pursue other therapeutic strategies, including stem cells and gene therapy, for which the mouse model will be critical.

Beyond progeria, these results have the potential to benefit all patients with cardiovascular disease. Researchers have discovered that the toxic protein responsible for progeria is actually produced at low levels in all humans, possibly accumulating as we age. Thus, by studying these rare children, Collins says, we can further our understanding of a major mechanism of human aging—and perhaps, find new ways to slow the process.