Journal of Molecular Neuroscience

, Volume 58, Issue 1, pp 46–58

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

  • Chen Benkler
  • Yael Barhum
  • Tali Ben-Zur
  • Daniel Offen
Article

DOI: 10.1007/s12031-015-0695-2

Cite this article as:
Benkler, C., Barhum, Y., Ben-Zur, T. et al. J Mol Neurosci (2016) 58: 46. doi:10.1007/s12031-015-0695-2

Abstract

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) Gene therapy Glutamate EAAT2 GDH2 NRF2 

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Chen Benkler
    • 1
  • Yael Barhum
    • 1
  • Tali Ben-Zur
    • 1
  • Daniel Offen
    • 1
    • 2
  1. 1.Felsenstein Medical Research Center, Sackler School of MedicineTel Aviv UniversityTel AvivIsrael
  2. 2.Felsenstein Medical Research CenterRabin Medical CenterPetah TikvaIsrael