title: Systemic AAV6 delivery mediating RNA interference against SOD1: neuromuscular transduction does not alter disease progression in fALS mice.
abstract: 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. With the aim of maximizing the delivery of these silencing instructions, we explored the efficacy of intravenous delivery of recombinant adeno-associated virus (rAAV) serotype 6 expressing small hairpin RNAs targeting mutant SOD1 in the G93A SOD1 fALS mouse model. This approach resulted in a systemic transduction profile, corresponding to transduction of the entire skeletal musculature as well as heart and liver. In addition, motor neurons at all levels of the spinal cord and brain stem were transduced, amounting to 3-5% of the lower motor neuron pool. 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.
authors.affiliation: Brain Mind Institute, School of Life Science, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Chris
authors.initials: C
authors.lastname: Towne
authors.forename: Cédric
authors.initials: C
authors.lastname: Raoul
authors.forename: Bernard L
authors.initials: BL
authors.lastname: Schneider
authors.forename: Patrick
authors.initials: P
authors.lastname: Aebischer
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000628:therapy*; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D018450:Disease Progression; D008099:Liver / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D034622:RNA Interference; D013116:Spinal Cord / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1
chemical_list: C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1