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

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.

Author information

1
Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
2
Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. danieloffen@gmail.com.
3
Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, 49100, Israel. danieloffen@gmail.com.

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); EAAT2; GDH2; Gene therapy; Glutamate; NRF2

PMID:
26691332
DOI:
10.1007/s12031-015-0695-2
[Indexed for MEDLINE]

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