title: Rescue of amyotrophic lateral sclerosis phenotype in a mouse model by intravenous AAV9-ADAR2 delivery to motor neurons.
abstract: Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease, and the lack of effective therapy results in inevitable death within a few years of onset. Failure of GluA2 RNA editing resulting from downregulation of the RNA-editing enzyme adenosine deaminase acting on RNA 2 (ADAR2) occurs in the majority of ALS cases and causes the death of motor neurons via a Ca(2+) -permeable AMPA receptor-mediated mechanism. Here, we explored the possibility of gene therapy for ALS by upregulating ADAR2 in mouse motor neurons using an adeno-associated virus serotype 9 (AAV9) vector that provides gene delivery to a wide array of central neurons after peripheral administration. A single intravenous injection of AAV9-ADAR2 in conditional ADAR2 knockout mice (AR2), which comprise a mechanistic mouse model of sporadic ALS, caused expression of exogenous ADAR2 in the central neurons and effectively prevented progressive motor dysfunction. Notably, AAV9-ADAR2 rescued the motor neurons of AR2 mice from death by normalizing TDP-43 expression. This AAV9-mediated ADAR2 gene delivery may therefore enable the development of a gene therapy for ALS.
authors.affiliation: CREST, Japan Science and Technology Agency, Graduate School of Medicine, University of Tokyo, Bunkyo-Ku, Tokyo, Japan; Department of Neurology, Graduate School of Medicine, University of Tokyo, Bunkyo-Ku, Tokyo, Japan; Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-Ku, Tokyo, Japan.
authors.forename: Takenari
authors.initials: T
authors.lastname: Yamashita
authors.forename: Hui Lin
authors.initials: HL
authors.lastname: Chai
authors.forename: Sayaka
authors.initials: S
authors.lastname: Teramoto
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
authors.forename: Kuniko
authors.initials: K
authors.lastname: Shimazaki
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Muramatsu
authors.forename: Shin
authors.initials: S
authors.lastname: Kwak
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics* / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics / Q000628:therapy; D000818:Animals; D001921:Brain / Q000166:cytology / Q000201:enzymology / Q000821:virology; D000229:Dependovirus / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000502:physiology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000201:enzymology*; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D016601:RNA-Binding Proteins; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase
keywords: AMPA receptor; adeno-associated virus (AAV) 9; adenosine deaminase acting on RNA 2 (ADAR2); amyotrophic lateral sclerosis (ALS); gene therapy