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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

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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.

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Authors and Affiliations

  1. Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Chen Benkler, Yael Barhum, Tali Ben-Zur & Daniel Offen

  2. Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, 49100, Israel

    Daniel Offen

Authors
  1. Chen Benkler
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  2. Yael Barhum
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  3. Tali Ben-Zur
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  4. Daniel Offen
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Corresponding author

Correspondence to Daniel Offen.

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Funding

The study was partially supported by Prize4life.

Conflict of Interest

D. O. is a consultant in Brainstorm Cell Therapeutics, Israel. C.B and D.O. have registered a patent on this issue. The other authors declare no conflict of interest.

Animal Care

The experiments were performed in accordance with local and international regulations, and were approved by the Tel Aviv University Ethical Committee. Every effort was made to reduce the number of animals used and to minimize their suffering.

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Benkler, C., Barhum, Y., Ben-Zur, T. et al. 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 58, 46–58 (2016). https://doi.org/10.1007/s12031-015-0695-2

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  • DOI: https://doi.org/10.1007/s12031-015-0695-2

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