In 1998, Leslie Gordon's toddler son Sam was diagnosed with an exceedingly rare and invariably fatal disease, Hutchinson-Gilford progeria syndrome, which in many ways resembles premature aging. Immediately, Gordon, a physician, decided to do everything she could to change the dismal outlook for the disease, in which the average age of death is 13: She acquired a Ph.D. and formed a foundation that has allocated millions for progeria research. This week, Gordon co-authors a publication that describes the first clinical trial of a drug for progeria. She's optimistic that the drug helped the children, including Sam, who participated. But others say the results are difficult to interpret and it's not clear the therapy made a difference.
Hutchinson-Gilford progeria is caused by a spontaneous mutation during conception in a gene called LMNA, which encodes a protein called prelamin A. Progeria patients experience a buildup of an abnormal version of prelamin A in their cells that, among other changes, distorts the nucleus and alters gene expression. Although they look normal at birth, toddlers with progeria don't grow properly, and just like elderly people, they begin to lose hair and body fat, and suffer joint stiffness and atherosclerosis. In 2005, a group led by Stephen Young, a cardiologist at the University of California, Los Angeles, showed that a class of drugs called farnesyltransferase inhibitors (FTIs) seemed to normalize cells with progeria, and in 2006 his team reported similar success in a mouse model of the disease.
Gordon's The Progeria Research Foundation launched a trial of one FTI called lonafarnib, which had been tested without success in cancer. Twenty-five children—who comprise 75% of those known to have the disease worldwide when the trial began—were closely tracked for at least 2 years on lonafarnib. To measure success, the researchers focused on weight gain, which in kids with progeria progresses at a snail's pace. In the trial, nine children had a median weight gain of 0.52 kilograms per year, or just over a pound, an improvement over essentially no weight gain the year before. The other 16 children either had no significant change in their rate of weight gain or lost weight during the study. Results were published online today in the Proceedings of the National Academy of Sciences.
Gordon is excited not only about the weight gain but also by a measure of arterial stiffening assessed in 18 of the children. In all but one, the measure improved, suggesting the vessel had become more flexible and potentially reducing the risk of heart attacks and strokes. "We can change something about the cardiovascular system that has implications for health," Gordon says.
Others aren't so sure. "I worry that we're interpreting noise" in the data, rather than seeing actual evidence of benefits, says Harry Dietz, a pediatric cardiologist at Johns Hopkins University in Baltimore, Maryland. "It's a complex paper and very difficult to interpret in my opinion," agrees Nicolas Lévy, head of molecular genetics at the Timone Children's Hospital in Marseille, France, who helped lead a group that identified the gene mutation behind progeria in 2003.
The Progeria Research Foundation's lonafarnib trial ended in 2010, but the foundation is now monitoring 45 children from 24 countries who are taking the drug, as well as the cholesterol drug pravastatin and zoledronate, which prevents fractures. Both normalized progeria cells in a dish and treated mice with a version of the disease. Lévy and colleagues are currently conducting a separate trial, testing the latter two drugs on 12 children with progeria. They hope to report their results soon.
An expanded version of this story will appear in the 28 September issue of Science.