title: Viral delivery of antioxidant genes as a therapeutic strategy in experimental models of amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with no effective treatment to date. Despite its multi-factorial aetiology, oxidative stress is hypothesized to be one of the key pathogenic mechanisms. It is thus proposed that manipulation of the expression of antioxidant genes that are downregulated in the presence of mutant SOD1 may serve as a therapeutic strategy for motor neuronal protection. Lentiviral vectors expressing either PRDX3 or NRF2 genes were tested in the motor neuronal-like NSC34 cell line, and in the ALS tissue culture model, NSC34 cells expressing the human SOD1(G93A) mutation. The NSC34 SOD1(G93A) cells overexpressing either PRDX3 or NRF2 showed a significant decrease in endogenous oxidation stress levels by 40 and 50% respectively compared with controls, whereas cell survival was increased by 30% in both cases. The neuroprotective potential of those two genes was further investigated in vivo in the SOD1(G93A) ALS mouse model, by administering intramuscular injections of adenoassociated virus serotype 6 (AAV6) expressing either of the target genes at a presymptomatic stage. Despite the absence of a significant effect in survival, disease onset or progression, which can be explained by the inefficient viral delivery, the promising in vitro data suggest that a more widespread CNS delivery is needed.
authors.affiliation: Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Nanou
authors.forename: Adrian
authors.initials: A
authors.lastname: Higginbottom
authors.forename: Chiara F
authors.initials: CF
authors.lastname: Valori
authors.forename: Matthew
authors.initials: M
authors.lastname: Wyles
authors.forename: Ke
authors.initials: K
authors.lastname: Ning
authors.forename: Pamela
authors.initials: P
authors.lastname: Shaw
authors.forename: Mimoun
authors.initials: M
authors.lastname: Azzouz
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000628:therapy; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002460:Cell Line; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics*; D061105:Peroxiredoxin III / Q000235:genetics; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic; D019076:Transgenes
chemical_list: D051267:NF-E2-Related Factor 2; D061105:Peroxiredoxin III; D013482:Superoxide Dismutase