RNA Silencing of SOD1 Preserves Strength in Mouse Model of ALS

NEW YORK (Reuters Health) - Intramuscular injections of a viral vector encoding short interfering RNA (siRNA) directed against superoxide dismutase (SOD1) delays the loss of grip strength in a mouse model of amyotrophic lateral sclerosis (ALS), investigators report in the May Annals of Neurology.

Mutations in SOD1 cause one form of dominantly inherited ALS in humans, senior investigator Dr. Don W. Cleveland and his colleagues note. Transgenic mice that overexpress mutant SOD1 develop symptoms that resemble ALS in humans.

To test the efficacy of treatment with siRNA, Dr. Cleveland, at the University of California, San Diego, in La Jolla and his team designed an adeno-associated virus (AAV-2) that carried green fluorescent protein (GFP) and siRNA directed against SOD1 or a 2 base-pair missense control. They then injected the lower part of the hind limb on one side of SOD1 mutant mice with one of the two AAV-2 viruses and tested the animals weekly with a grip strength meter.

GFP was found in the spinal cord of all the injected animals, demonstrating retrograde transport of the virus, the authors note, and motor neurons expressing GFP had lower levels of SOD1.

Only the limbs of the mice that were treated with the SOD1-directed siRNA showed "remarkable preservation of grip strength," compared with the non-injected control limb.

"We anticipate that reduction in mutant SOD1 by AAV-2-mediated delivery of siRNA after peripheral injection may be an effective therapy for SOD1 familial ALS patients," Dr. Cleveland and his associates maintain.

Ann Neurol 2005;57:773-776.