Rescue of amyotrophic lateral sclerosis phenotype in a mouse model by intravenous AAV9-ADAR2 delivery to motor neurons

EMBO Mol Med. 2013 Nov;5(11):1710-9. doi: 10.1002/emmm.201302935. Epub 2013 Sep 24.

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.

Keywords: AMPA receptor; adeno-associated virus (AAV) 9; adenosine deaminase acting on RNA 2 (ADAR2); amyotrophic lateral sclerosis (ALS); gene therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Deaminase / genetics*
  • Adenosine Deaminase / metabolism
  • Amyotrophic Lateral Sclerosis / enzymology*
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / therapy
  • Animals
  • Brain / cytology
  • Brain / enzymology
  • Brain / virology
  • Dependovirus / genetics
  • Dependovirus / physiology
  • Disease Models, Animal
  • Genetic Therapy*
  • Genetic Vectors / genetics
  • Genetic Vectors / physiology
  • Humans
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Motor Neurons / enzymology*
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism

Substances

  • RNA-Binding Proteins
  • ADARB1 protein, human
  • Adenosine Deaminase