Combined Gene Therapy to Reduce the Neuronal Damage in the Mouse Model of Focal Ischemic Injury
- 74 Downloads
Research into stroke is driven by frustration over the limited available therapeutics. Targeting a single aspect of this multifactorial disease contributes to the therapeutic boundaries. To overcome this, we devised a novel multifactorial-cocktail treatment, using lentiviruses encoding excitatory amino acid transporter 2 (EAAT2(, glutamate dehydrogenase 2 (GDH2), and nuclear factor E2-related factor 2 (Nrf2) genes, that acts synergistically to address the effected excito-oxidative axis. Here, we used the vasoconstrictor endothelin-1 (ET-1) to induce focal ischemic injury in mice by direct injection into the striatum. Mice treated with the mixture of these three genes show significant improvement in body balance, motor coordination, and decreased motor asymmetry compared to each gene separately. These results demonstrate that overexpression of the combined EAAT2, GDH2, and NRF2 genes can provide neuroprotection after ischemic injury.
KeywordsStroke Ischemic injury Gene therapy EAAT2 GDH2 Nrf2
This study received funds as a scholarship from Mr. Martin Davis to LM.
Compliance with Ethical Standards
DO holds several patents related to gene therapy in neurodegenerative diseases. All were assigned to “Ramot at Tel Aviv University.” DO is a consultant to “Brainstorm Cell Therapeutics.” The other authors have nothing to disclose.
- Begum G, Song S, Wang S, Zhao H, Bhuiyan MIH, Li E, Nepomuceno R, Ye Q, Sun M, Calderon MJ, Stolz DB, St. Croix C, Watkins SC, Chen Y, He P, Shull GE, Sun D (2018) Selective knockout of astrocytic Na1/H1 exchanger isoform 1 reduces astrogliosis, BBB damage, infarction, and improves neurological function after ischemic stroke. Glia 66:126–144CrossRefPubMedGoogle Scholar
- Harvey BK, Airavaara M, Hinzman J, Wires EM, Chiocco MJ, Howard DB, Shen H, Gerhardt G, Hoffer BJ, Wang Y (2011) Targeted over-expression of glutamate transporter 1 (GLT-1) reduces ischemic brain injury in a rat model of stroke. PLoS One 6(8). https://doi.org/10.1371/journal.pone.0022135 CrossRefPubMedPubMedCentralGoogle Scholar
- Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, Oyake T, Hayashi N, Satoh K, Hatayama I, Yamamoto M, Nabeshima Y (1997) An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun 236(2):313–322CrossRefPubMedGoogle Scholar
- Matsui T, Mori T, Tateishi N, Kagamiishi Y, Satoh S, Katsube N, Morikawa E, Morimoto T, Ikuta F, Asano T (2002) Astrocytic activation and delayed infarct expansion after permanent focal ischemia in rats. Part I: enhanced astrocytic synthesis of S-100?? In the periinfarct area precedes delayed infarct expansion. J Cereb Blood Flow Metab 22:711–722CrossRefPubMedGoogle Scholar
- Plaitakis A, Metaxari M, Shashidharan P (2000) Nerve tissue-specific (GLUD 2) and housekeeping (GLUD 1) human glutamate dehydrogenases are regulated by distinct allosteric mechanisms : implications for biologic function. J Neurochem 75(5):1862–1869Google Scholar