Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of motor neurons, resulting in progressive muscle weakness, paralysis, and death within 5 years of diagnosis. About 10% of cases are inherited, of which 20% are due to mutations in the superoxide dismutase 1 (SOD1) gene. Riluzole, the only US Food and Drug Administration–approved ALS drug, prolongs survival by only a few months. Experiments in transgenic ALS mouse models have shown decreasing levels of mutant SOD1 protein as a potential therapeutic approach. We sought to develop an efficient adeno‐associated virus (AAV)‐mediated RNAi gene therapy for ALS.

A single‐stranded AAV9 vector encoding an artificial microRNA against human SOD1 was injected into the cerebral lateral ventricles of neonatal SOD1^G93A mice, and impact on disease progression and survival was assessed.

This therapy extended median survival by 50% and delayed hindlimb paralysis, with animals remaining ambulatory until the humane endpoint, which was due to rapid body weight loss. AAV9‐treated SOD1^G93A mice showed reduction of mutant human SOD1 mRNA levels in upper and lower motor neurons and significant improvements in multiple parameters including the numbers of spinal motor neurons, diameter of ventral root axons, and extent of neuroinflammation in the SOD1^G93A spinal cord. Mice also showed previously unexplored changes in pulmonary function, with AAV9‐treated SOD1^G93A mice displaying a phenotype reminiscent of patient pathophysiology.

These studies clearly demonstrate that an AAV9‐delivered SOD1‐specific artificial microRNA is an effective and translatable therapeutic approach for ALS. Ann Neurol 2016;79:687–700