title: Therapeutic AAV9-mediated suppression of mutant SOD1 slows disease progression and extends survival in models of inherited ALS.
abstract: Mutations in superoxide dismutase 1 (SOD1) are linked to familial amyotrophic lateral sclerosis (ALS) resulting in progressive motor neuron death through one or more acquired toxicities. Involvement of wild-type SOD1 has been linked to sporadic ALS, as misfolded SOD1 has been reported in affected tissues of sporadic patients and toxicity of astrocytes derived from sporadic ALS patients to motor neurons has been reported to be reduced by lowering the synthesis of SOD1. We now report slowed disease onset and progression in two mouse models following therapeutic delivery using a single peripheral injection of an adeno-associated virus serotype 9 (AAV9) encoding an shRNA to reduce the synthesis of ALS-causing human SOD1 mutants. Delivery to young mice that develop aggressive, fatal paralysis extended survival by delaying both disease onset and slowing progression. In a later-onset model, AAV9 delivery after onset markedly slowed disease progression and significantly extended survival. Moreover, AAV9 delivered intrathecally to nonhuman primates is demonstrated to yield robust SOD1 suppression in motor neurons and glia throughout the spinal cord and therefore, setting the stage for AAV9-mediated therapy in human clinical trials.
authors.affiliation: Department of Neuroscience, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Foust
authors.forename: Desirée L
authors.initials: DL
authors.lastname: Salazar
authors.forename: Shibi
authors.initials: S
authors.lastname: Likhite
authors.forename: Laura
authors.initials: L
authors.lastname: Ferraiuolo
authors.forename: Dara
authors.initials: D
authors.lastname: Ditsworth
authors.forename: Hristelina
authors.initials: H
authors.lastname: Ilieva
authors.forename: Kathrin
authors.initials: K
authors.lastname: Meyer
authors.forename: Leah
authors.initials: L
authors.lastname: Schmelzer
authors.forename: Lyndsey
authors.initials: L
authors.lastname: Braun
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kaspar
mesh_terms: D061605:Administration, Intravenous; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D057809:HEK293 Cells; D006801:Humans; D007278:Injections, Spinal; D008252:Macaca fascicularis; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics*; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D034741:RNA, Small Interfering; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1