AAV NRF2 Gene Therapy Preserves Retinal Structure and Function in Rodent Models of Oxidative Damage

Dry age-related macular degeneration is the most frequent cause of visual impairment in individuals over age 50 in developed countries. It is characterized by subretinal deposits of oxidized proteins and lipids and results in progressive loss of high acuity vision. One major risk factor is smoking, which causes oxidative stress in many tissues, including the eye. We previously showed that an adeno-associated viral vector expressing human NRF2 (AAV8/Best1-Nrf2), a transcription factor that regulates responses to oxidative damage, slowed degeneration in mouse models of another blinding disorder, retinitis pigmentosa, which also includes oxidative stress. Here, our AAV8/Best1-Nrf2 vector was tested in a model of oxidative stress wherein sodium iodate was injected systemically, as this is often used to model dry age-related macular degeneration. Sodium iodate causes acute oxidative damage to supporting cells of the retina, the retinal pigment epithelial cells, and ultimately leads to photoreceptor death. Subretinal injection of AAV8/Best1-Nrf2 led to protection of the retinal pigment epithelium and photoreceptors, as well as preservation of visual function, in rat and mouse sodium iodate models. AAV8/Best1-Nrf2 may serve as an effective gene-agnostic therapy for diseases with oxidative stress, including dry age-related macular degeneration. ETOC Oxidative stress occurs in diseases that lead to vision loss, including age-related macular degeneration (AMD). AMD is commonly modeled by injection of sodium iodate (S.I.), an oxidizing agent. AAV-mediated delivery of Nrf2, a transcription factor that regulates oxidative stress, protects the eye from S.I. damage in rat and mouse models.