A drug approved to treat cancer and prevent the rejection of transplanted organs may also help children with progeria—a disease that resembles accelerated aging and typically kills those afflicted by their teens—according to a new study. The drug's effects on cells from these children is so striking, and the condition so devastating, that physicians and scientists are debating whether to proceed immediately with a clinical trial.
Hutchinson-Gilford progeria syndrome (HGPS), commonly called progeria, is an incredibly rare genetic disorder, fewer than 100 children currently are diagnosed with it worldwide. It has gained notoriety because the children, despite looking healthy for the first year or so of life, develop apparent age-related features such as stiff skin, loss of hair, fragile bones, and cardiovascular disease. The condition remained almost a complete mystery until 2003 when two groups, one including geneticist Francis Collins, now director of the U.S. National Institutes of Health, and physician-scientist Leslie Gordon, a parent of a boy with HGPS, identified a mutation in progeria children.
The genetic defect disrupts the processing of a protein called lamin A that helps shape a cell's nucleus. As a result, cells produce large amounts of an abnormal form of lamin A dubbed progerin, and the typically oval nuclei blister and buckle. Somehow the progerin buildup disrupts development of many of the children's tissues. Three drugs that impair the creation of progerin are already being tested on about 50 children with progeria.
Seeking a drug that works through a different mechanism and that might complement the other experimental medicines, several groups studying progeria have recently turned to rapamycin, a compound with diverse actions, including suppressing the immune system. In 2009, a research team showed that administering rapamycin could extend the life span of mice.
Might it therefore also help kids with progeria? When cells from children with the condition are exposed to the drug in lab dishes, they eliminate their abnormal buildup of progerin and survive longer, Collins, Kan Cao of the National Human Genome Research Institute, and colleagues report today in Science Translational Medicine. Furthermore, the nuclei in the progeria cells go from "pretty darn abnormal" to "very beautiful, happy-looking ovoids," Collins says.
Normal cells make small amounts of progerin, convincing many researchers that it contributes to natural aging, and the team found that rapamycin also promoted the protein's clearance in them. Rapamycin, Collins explains, inhibits the activity of a protein called mTOR and in doing so promotes a process called autophagy that eliminates abnormal proteins, including progerin. That's apparently enough for the nucleus to revert to its normal shape.
"This is a new approach worth pursuing" for treating progeria, Collins says. "We've now got a different way of attacking progerin," agrees Gordon, who was not affiliated with the study but is the medical director of the Progeria Research Foundation, which she and her husband started and which partially funded the rapamycin work. "This is fantastic news."
The difficult question now is how fast to move, given the short life span of kids with progeria. Some scientists urge further study. "What's lacking is any evidence that rapamycin is beneficial in a mouse model of the disease, which is an essential step before thinking about clinical trials," says molecular biologist Brian Kennedy, president of the Buck Institute for Research on Aging in Novato, California. He notes that the purely cellular studies in the new paper are hard to reconcile with findings on one strain of mice engineered to have progeria. In these rodents, autophagy is already in overdrive, so Kennedy is skeptical that rapamycin would help these animals—and thus children with progeria.
Not everyone shares Kennedy's reluctance. Gordon, for example, notes that rapamycin has well-known and relatively modest side effects and has been tested in many children already, so she and the others running the current progeria clinical trial are "seriously considering" whether to start giving an oral derivative of rapamycin to the children. Gordon says that the mouse model of progeria that worries Kennedy may not be the most accurate mimic of the human condition. And although some rapid testing of rapamycin's toxicity in mice with a form of progeria is warranted, "I'm not sure we would need to wait 2 to 3 years for an efficacy study in mice," she says.
Kennedy admits he would understand if Gordon, whose son with progeria is now 14 years old, and other physicians pushed ahead with a clinical trial. "The disease is so severe that there's an openness to trying a drug in the children," he says.