A trio of studies has found success with a new way to stall a devastating and incurable disease: amyotrophic lateral sclerosis (ALS), or Lou Gehrig's Disease. The strategy, called RNA interference (RNAi), has increasingly garnered attention as a way to shut down genes and manage various disorders.
ALS attacks motor neurons throughout the body, destroying a victim's ability to walk, speak, and breathe. Most sufferers die within 3 to 5 years. The disease comes in two forms, hereditary and sporadic. The hereditary variant makes up just 10% of all cases; in those cases, a defective gene, SOD1, is believed to churn out a protein that's toxic to neurons. Because hereditary ALS has been linked to defects in a particular gene, it's a prime candidate for RNAi studies.
Three independent teams of scientists set out to target SOD1 with RNAi. At the L'Ecole Polytechnique Fédérale de Lausanne in Switzerland, neuroscientist and president Patrick Aebischer and his colleagues injected RNA molecules encased in a viral shell into the lumbar spinal cord of six young mice with a mutated form of SOD1. The neuromuscular function of the treated mice was 40% better than controls, and it took them 20 days longer to develop symptoms of the disease. But because the injections didn't target areas higher in the spinal cord, the animals still died from loss of respiratory function.
Neurobiologist Mimoun Azzouz, Scott Ralph, and their colleagues at Oxford Biomedica in Oxford, U.K., tried a slightly different approach. They too used RNA encased in a viral shells, but instead targeted muscle groups that control feeding and diaphragm movement. Mice treated early developed symptoms at around 200 days of age, compared to 94 days for controls, and lived to around 228 days (80% of a normal mouse life span), compared to 129 for controls. Both Azzouz's and Aebischer's studies were published in the 14 March online Nature Medicine.
Finally, Don Cleveland at the University of California, San Diego, used a different virus—previously tested in human gene therapy trials--to carry his small RNA molecules. Unlike the other groups, Cleveland tested his therapy on older mice (though the animals were still too young to show many symptoms) and focused on one muscle of one hind limb. His finding, that the treated animals had better grip strength, is in press in the Annals of Neurology.
"The obvious question is what happens when you [treat] more diseased animals," says Beverly Davidson, who led mouse RNAi studies of spinocerebellar ataxia, another neurodegenerative disease. Still, she says, the consistency of the initial findings, across three labs and two viral vectors, is "incredibly promising."