RESEARCH NOTES
Gene Therapy in Mice Delays ALS

Scientists studying mice genetically engineered to develop familial amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, have found that the human gene Bcl-2 may delay the onset of the disease. The study appeared in a July issue of the journal Science.

ALS is the most common motor neuron disease in humans. Inherited ALS accounts for 15 percent of all cases of the disease, and patients have symptoms identical to the more common sporadic form. These include a progressive loss of motor neurons in the spinal cord that leads to muscle wasting, paralysis, and, ultimately, death. Currently, the only treatments for ALS are mechanical ventilation and, to a lesser extent, the drug riluzole.

Columbia researchers worked with two strains of transgenic mice: one carrying mutations that produced familial ALS and another carrying the human proto-oncogene Bcl-2, which is known to protect against apoptosis or cell death. The Bcl-2 mice carried 16 copies of the gene so that it would be "over expressed" to maximize any protective effect against ALS. Scientists cross-bred the two strains of mice and discovered that offspring inheriting both ALS and Bcl-2 developed ALS significantly later in life--and in fact lived longer--than offspring that inherited ALS but not Bcl-2.

The gene responsible for familial ALS is a mutant copper/zinc superoxide dismutase, which normally rids the body of free radicals, unstable chemicals produced during metabolism that damage cell membranes, DNA, and other constituents of cells. People with the mutation presumably develop ALS because of free radical damage to their motor neurons. The study found that ALS-mice carrying the Bcl-2 gene had more and healthier motor neurons than ALS-mice without Bcl-2.

"The study suggests that gene therapy--either with Bcl-2 or with another gene capable of preventing apoptosis--could help delay the onset of ALS," says Dr. Serge Przedborski, P&S assistant professor of neurology and principal investigator of the study. The finding could also lead to the development of drugs that mimic proteins produced by Bcl-2 or other protective genes. Columbia researchers and colleagues from Hôpitaux Universitaires de Genève collaborated on the study, which was funded by the National Institute of Neurological Disorders and Stroke and the Muscular Dystrophy Association.