Multifactorial Gene Therapy Enhancing the Glutamate Uptake System and Reducing Oxidative Stress Delays Symptom Onset and Prolongs Survival in the SOD1-G93A ALS Mouse Model

J Mol Neurosci. 2016 Jan;58(1):46-58. doi: 10.1007/s12031-015-0695-2. Epub 2015 Dec 21.


The 150-year-long search for treatments of amyotrophic lateral sclerosis (ALS) is still fueled by frustration over the shortcomings of available therapeutics. Contributing to the therapeutic limitations might be the targeting of a single aspect of this multifactorial-multisystemic disease. In an attempt to overcome this, we devised a novel multifactorial-cocktail treatment, using lentiviruses encoding: EAAT2, GDH2, and NRF2, that act synergistically to address the band and width of the effected excito-oxidative axis, reducing extracellular-glutamate and glutamate availability while improving the metabolic state and the anti-oxidant response. This strategy yielded particularly impressive results, as all three genes together but not separately prolonged survival in ALS mice by an average of 19-22 days. This was accompanied by improvement in every parameter evaluated, including body-weight loss, reflex score, neurologic score, and motor performance. We hope to provide a novel strategy to slow down disease progression and alleviate symptoms of patients suffering from ALS.

Keywords: Amyotrophic lateral sclerosis (ALS); EAAT2; GDH2; Gene therapy; Glutamate; NRF2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / therapy*
  • Animals
  • Cells, Cultured
  • Genetic Therapy*
  • Glutamate Plasma Membrane Transport Proteins / genetics*
  • Glutamate Plasma Membrane Transport Proteins / metabolism
  • Glutamic Acid / metabolism*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mutation, Missense
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism
  • Oxidative Stress*
  • Sugar Alcohol Dehydrogenases / genetics
  • Sugar Alcohol Dehydrogenases / metabolism
  • Superoxide Dismutase / genetics*
  • Superoxide Dismutase-1


  • Glutamate Plasma Membrane Transport Proteins
  • NF-E2-Related Factor 2
  • SOD1 protein, human
  • Glutamic Acid
  • Sugar Alcohol Dehydrogenases
  • galactitol 2-dehydrogenase
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1