Inhibiting Cell-Death Gene May Slow ALS Progression

ALS is a degenerative disorder of the brain and spinal cord, which causes weakness and wasting of muscles. Patients eventually become paralyzed and die, usually within five years. The gene that causes ALS when mutated was discovered in 1993 by researchers in MGH laboratory of Robert H. Brown Jr., MD, PhD, who is a coauthor of the current Nature paper. That gene codes for production of an enzyme called superoxide dismutase (SOD1), known to neutralize dangerous chemicals called free radicals in the body.

In the current study, the MGH researchers used two strains of transgenic mice with mutations in key genes. One strain with mutations in SOD1 develops an ALS-like muscle disease. The other strain has a specific mutation called M17Z in the gene coding for the ICE protein. Discovered in 1993 by a team of researchers from the MGH and the Massachusetts Institute of Technology, the ICE gene controls some instances of programmed cell death, a natural process in which cells not necessary for normal development essentially commit suicide. The leader of the group identifying the ICE gene was Junying Yuan, PhD, also a coauthor of the Nature paper.

The researchers crossed a group of SOD1 mutant mice with a group of M17Z/ICE mutant mice and determined which of their offspring carried mutations in both genes. While mice with both mutations developed ALS-like symptoms at about the same age as those mice with the SOD1 mutation only -- about 240 days old -- the mice with both mutations lived significantly longer after disease onset than those with the single mutation -- 27 days versus almost 12 days. The results suggest that inhibiting activity of the ICE gene could slow the progression of ALS in human patients.

"This result is the first indication of the genetic pathway which mediates cell death in ALS," says Robert M. Friedlander, MD, a resident in the MGH Neurosurgical Service, who is first author of the report. "This novel insight into cell death in ALS opens a new avenue of possible therapy using drugs that inhibit the ICE cell death gene family."

Yuan, who was a member of the MGH Cardiovascular Research Center (CVRC) when this research was began, now is in the Cell Biology Department at Harvard Medical School.