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AAV-Nrf2 Promotes Protection and Recovery in Animal Models of Oxidative Stress

Liang, Katharine J. ; Woodard, Kenton T. ; Weaver, Mark A. ; Gaylor, John Paul ; Weiss, Ellen R. ; Samulski, R. Jude

Molecular therapy, 2017-03, Vol.25 (3), p.765-779 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
AAV-Nrf2 Promotes Protection and Recovery in Animal Models of Oxidative Stress
Autor: Liang, Katharine J. ; Woodard, Kenton T. ; Weaver, Mark A. ; Gaylor, John Paul ; Weiss, Ellen R. ; Samulski, R. Jude
Assuntos: AAV ; Acetaminophen ; Acetaminophen - pharmacology ; Age ; Analgesics ; Animal models ; Animals ; antioxidant ; Antioxidants ; Chronic illnesses ; Clinical outcomes ; Cloning ; Dependovirus - genetics ; Design ; Disease ; Experiments ; Gene Expression ; Gene Order ; Gene therapy ; Genetic Vectors - administration & dosage ; Genetic Vectors - genetics ; Grants ; Hepatotoxicity ; Histology ; Homeostasis ; Humans ; Injection ; Intravitreal Injections ; Light ; light damage ; Liver ; Liver - drug effects ; Liver - metabolism ; Liver - pathology ; Macular degeneration ; Mice ; Mice, Knockout ; Microscopy ; Models, Animal ; Mutation ; NF-E2-Related Factor 2 - genetics ; Nrf2 ; Original ; Oxidative stress ; Oxidative Stress - genetics ; Pathogenesis ; Reactive Oxygen Species ; Recovery of function ; Response Elements ; Retina ; Retina - metabolism ; Retina - radiation effects ; retinopathy ; Statistical analysis ; Studies ; Time Factors ; Transduction, Genetic
É parte de: Molecular therapy, 2017-03, Vol.25 (3), p.765-779
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Descrição: 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. [Display omitted] Liang et al. utilize adeno-associated virus (AAV)-mediated delivery of the Nrf2 transcription factor to activate the antioxidant response element to confer protection from oxidative stress in two distinct mouse models. AAV-Nrf2 confers survival benefit in acetaminophen-induced hepatotoxicity as well as protection from structural and functional damage in light-induced retinopathy.
Editor: United States: Elsevier Inc
Idioma: Inglês

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AAV-Nrf2 Promotes Protection and Recovery in Animal Models of Oxidative Stress

Liang, Katharine J. ; Woodard, Kenton T. ; Weaver, Mark A. ; Gaylor, John Paul ; Weiss, Ellen R. ; Samulski, R. Jude

United States: Elsevier Inc

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