A class of drugs already under development for cancer may offer the first treatment for Hutchinson-Gilford progeria syndrome (HGPS), a rare genetic disorder in which children seem to age prematurely and typically die in their teens. Two research groups report this week that the drugs reverse a key cellular defect characteristic of the syndrome.
HGPS is caused by mutations in the gene encoding lamin A, a key component of a matrix of proteins that lie just inside the cell's nuclear membrane. At an early age, those born with such mutations develop osteoporosis, atheroscelerosis, wizened skin, hair loss, and other features typical of the elderly. Scientists have also noticed that the cell nuclei of HGPS patients bulge in odd ways, apparently because the abnormal lamin A generated by the mutation accumulates near the nuclear membrane and distorts it.
Enzymes called farnesyltransferases help lamin A get to the nuclear membrane in the first place, so Francis Collins of the National Human Genome Research Institute (NHGRI) in Bethesda, Maryland, and others speculated that inhibiting these enzymes could help HGPS patients. Earlier this year, a group led by Stephen Young and Loren Fong, both of the University of California, Los Angeles, showed that such inhibitors, originally designed to keep farnesyltransferases from activating cancer-promoting proteins, could reverse the misshapen nuclei in cells from mice with mutations in the lamin A gene.
Now, in a paper published online this week in Proceedings of the National Academy of Sciences (PNAS), the group reports similar results with skin cells from HGPS patients. In a second PNAS paper, Collins, along with NHGRI's Brian Capell and colleagues, report comparable findings.
While it's not yet known if these drugs can slow or cure the disorder in humans, scientists are so encouraged by the cell studies that they are readying plans for a clinical trial next year. "I figured this was a long shot, and at best you might see a small effect," says Collins. "Instead, what you see, looking at the shape of the nucleus, is that you can cure these cells."
Still, Collins, Young, and others caution that it's not proven that the nuclear distortions cause the premature aging disease. Cell biologist Robert Goldman of Northwestern University Institute for Neuroscience in Chicago agrees. "I'm not sure [preventing] misshapen nuclei alone is the answer," he says, noting that lamins have many roles beyond giving the nucleus its spherical form.