title: 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.
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.
authors.affiliation: Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Chen
authors.initials: C
authors.lastname: Benkler
authors.affiliation: Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Barhum
authors.affiliation: Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Tali
authors.initials: T
authors.lastname: Ben-Zur
authors.affiliation: Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. danieloffen@gmail.com.|Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, 49100, Israel. danieloffen@gmail.com.
authors.forename: Daniel
authors.initials: D
authors.lastname: Offen
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000628:therapy*; D000818:Animals; D002478:Cells, Cultured; D015316:Genetic Therapy; D050491:Glutamate Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D013401:Sugar Alcohol Dehydrogenases / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1
chemical_list: D050491:Glutamate Plasma Membrane Transport Proteins; D051267:NF-E2-Related Factor 2; C000606290:SOD1 protein, human; D018698:Glutamic Acid; D013401:Sugar Alcohol Dehydrogenases; C095946:galactitol 2-dehydrogenase; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: Amyotrophic lateral sclerosis (ALS); EAAT2; GDH2; Gene therapy; Glutamate; NRF2