TY - JOUR
T1 - 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
AU - Benkler, Chen
AU - Barhum, Yael
AU - Ben-Zur, Tali
AU - Offen, Daniel
N1 - Publisher Copyright: © 2015, Springer Science+Business Media New York.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - 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.
AB - 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.
KW - Amyotrophic lateral sclerosis (ALS)
KW - EAAT2
KW - GDH2
KW - Gene therapy
KW - Glutamate
KW - NRF2
UR - http://www.scopus.com/inward/record.url?scp=84957581988&partnerID=8YFLogxK
U2 - https://doi.org/10.1007/s12031-015-0695-2
DO - https://doi.org/10.1007/s12031-015-0695-2
M3 - مقالة
SN - 0895-8696
VL - 58
SP - 46
EP - 58
JO - Journal of Molecular Neuroscience
JF - Journal of Molecular Neuroscience
IS - 1
ER -