title: Therapeutic rAAVrh10 Mediated SOD1 Silencing in Adult SOD1(G93A) Mice and Nonhuman Primates.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease; survival in ALS is typically 3-5 years. No treatment extends patient survival by more than three months. Approximately 20% of familial ALS and 1-3% of sporadic ALS patients carry a mutation in the gene encoding superoxide dismutase 1 (SOD1). In a transgenic ALS mouse model expressing the mutant SOD1(G93A) protein, silencing the SOD1 gene prolongs survival. One study reports a therapeutic effect of silencing the SOD1 gene in systemically treated adult ALS mice; this was achieved with a short hairpin RNA, a silencing molecule that has raised multiple safety concerns, and recombinant adeno-associated virus (rAAV) 9. We report here a silencing method based on an artificial microRNA termed miR-SOD1 systemically delivered using adeno-associated virus rAAVrh10, a serotype with a demonstrated safety profile in CNS clinical trials. Silencing of SOD1 in adult SOD1(G93A) transgenic mice with this construct profoundly delayed both disease onset and death in the SOD1(G93A) mice, and significantly preserved muscle strength and motor and respiratory functions. We also document that intrathecal delivery of the same rAAVrh10-miR-SOD1 in nonhuman primates significantly and safely silences SOD1 in lower motor neurons. This study supports the view that rAAVrh10-miR-SOD1 merits further development for the treatment of SOD1-linked ALS in humans.
authors.affiliation: 1 Gene Therapy Center, University of Massachusetts Medical School , Worcester, Massachusetts.
authors.forename: Florie
authors.initials: F
authors.lastname: Borel
authors.affiliation: 1 Gene Therapy Center, University of Massachusetts Medical School , Worcester, Massachusetts.
authors.forename: Gwladys
authors.initials: G
authors.lastname: Gernoux
authors.affiliation: 1 Gene Therapy Center, University of Massachusetts Medical School , Worcester, Massachusetts.
authors.forename: Brynn
authors.initials: B
authors.lastname: Cardozo
authors.affiliation: 2 Department of Neurology, University of Massachusetts Medical School , Worcester, Massachusetts.
authors.forename: Jake P
authors.initials: JP
authors.lastname: Metterville
authors.affiliation: 1 Gene Therapy Center, University of Massachusetts Medical School , Worcester, Massachusetts.|2 Department of Neurology, University of Massachusetts Medical School , Worcester, Massachusetts.
authors.forename: Gabriela C
authors.initials: GC
authors.lastname: Toro Cabrera
authors.affiliation: 1 Gene Therapy Center, University of Massachusetts Medical School , Worcester, Massachusetts.
authors.forename: Lina
authors.initials: L
authors.lastname: Song
authors.affiliation: 3 Vector Core, University of Massachusetts Medical School , Worcester, Massachusetts.
authors.forename: Qin
authors.initials: Q
authors.lastname: Su
authors.affiliation: 1 Gene Therapy Center, University of Massachusetts Medical School , Worcester, Massachusetts.|3 Vector Core, University of Massachusetts Medical School , Worcester, Massachusetts.
authors.forename: Guang Ping
authors.initials: GP
authors.lastname: Gao
authors.affiliation: 1 Gene Therapy Center, University of Massachusetts Medical School , Worcester, Massachusetts.|4 Department of Pediatrics, University of Massachusetts Medical School , Worcester, Massachusetts.
authors.forename: Mai K
authors.initials: MK
authors.lastname: Elmallah
authors.affiliation: 2 Department of Neurology, University of Massachusetts Medical School , Worcester, Massachusetts.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
authors.affiliation: 1 Gene Therapy Center, University of Massachusetts Medical School , Worcester, Massachusetts.|4 Department of Pediatrics, University of Massachusetts Medical School , Worcester, Massachusetts.
authors.forename: Christian
authors.initials: C
authors.lastname: Mueller
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D009154:Mutation; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000627:therapeutic use; D000072105:Superoxide Dismutase-1
chemical_list: C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1