title: AAV-Nrf2 Promotes Protection and Recovery in Animal Models of Oxidative Stress.
abstract: NRF2 is a transcription factor that drives antioxidant gene expression in multiple organ systems. We hypothesized that Nrf2 overexpression could be therapeutically applied toward diseases in which redox homeostasis is disrupted. In this study, adeno-associated virus (AAV)-Nrf2 was tested in a mouse model of acute acetaminophen-induced liver toxicity and successfully conferred protection from hepatotoxicity, validating the vector design and early onset of NRF2-mediated protection. Furthermore, therapeutic potential of AAV-Nrf2 in chronic disease also was tested in a light-induced mouse model of age-related macular degeneration. Adult BALB/c mice were intravitreally injected with AAV-Nrf2 and subject to light damage following injection. Retinal thickness and function were monitored following light damage using optical coherence tomography and electroretinography, respectively. By 3 months post-damage, injected eyes had greater retinal thickness compared to uninjected controls. At 1 month post-damage, AAV-Nrf2 injection facilitated full functional recovery from light damage. Our results suggest a therapeutic potential for Nrf2 overexpression in acute and long-term capacities in multiple organ systems, opening up doors for combination gene therapy where replacement gene therapy requires additional therapeutic support to prevent further degeneration.
authors.affiliation: Gene Therapy Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Katharine J
authors.initials: KJ
authors.lastname: Liang
authors.affiliation: Gene Therapy Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Kenton T
authors.initials: KT
authors.lastname: Woodard
authors.affiliation: Departments of Medicine and Biostatistics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Weaver
authors.affiliation: Gene Therapy Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: John Paul
authors.initials: JP
authors.lastname: Gaylor
authors.affiliation: Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Ellen R
authors.initials: ER
authors.lastname: Weiss
authors.affiliation: Gene Therapy Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: rjs@med.unc.edu.
authors.forename: R Jude
authors.initials: RJ
authors.lastname: Samulski
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology; D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D015870:Gene Expression; D023061:Gene Order; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D006801:Humans; D058449:Intravitreal Injections; D008027:Light; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics*; D017382:Reactive Oxygen Species; D020218:Response Elements; D012160:Retina / Q000378:metabolism / Q000528:radiation effects; D013997:Time Factors; D014161:Transduction, Genetic
chemical_list: D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D000082:Acetaminophen
keywords: AAV; Nrf2; acetaminophen; antioxidant; gene therapy; light damage; liver; oxidative stress; retina; retinopathy