Molecular therapy : the journal of the American Society of Gene Therapy
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder arising from the selective death of motor neurons. Approximately 20% of familial ALS (fALS) cases are caused by toxic gain-of-function mutations in the superoxide dismutase 1 (SOD1) gene. We as well as others have provided proof-of-principle for the use of RNA interference (RNAi) against mutant SOD1 as a potential therapy for fALS. ⋯ SOD1 protein levels were reduced by >50% in all the muscles that were examined. Crucially, this silencing profile did not alter the course of the disease in this fALS model, thereby providing compelling evidence that SOD1-mediated damage within skeletal muscles does not contribute to death of motor neurons in ALS. Further, this study demonstrates that motor neurons can be transduced across the length of the spinal cord through a single noninvasive delivery of rAAV.