rAAV-Mediated Dual Gene Therapy Targeting Oxidative Stress and Complement Activation in a Mouse Model of NaIO3-Induced Retinal Degeneration

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss worldwide, with dry AMD representing the predominant form of the disease, although effective treatments remain limited. The pathogenesis of dry AMD involves dysregulation of the complement system and impaired antioxidant defenses, contributing to retinal pigment epithelium (RPE) and photoreceptor degeneration. Given the multifactorial nature of the disease, targeting a single pathological pathway may not adequately address its complexity. Here, we developed a single recombinant adeno-associated virus serotype 8 (rAAV8) vector designed to overexpress nuclear factor erythroid 2-related factor 2 (NRF2) while knocking down complement component 3 (C3). In an in vitro screen using ARPE-19 cells, NRF2 overexpression provided the strongest protection against sodium iodate (NaIO3)-induced oxidative injury among the antioxidant candidates tested. We subsequently evaluated the dual-target vector in a mouse model of NaIO3-induced retinal degeneration. Compared with NaIO3-injured controls, the combination group showed significant improvements in electroretinographic responses and better preservation of retinal architecture. NRF2-containing treatment groups showed more favorable outcomes than shC3 monotherapy. Direct comparisons with NRF2 monotherapy revealed significant additional benefits of the combination for selected endpoints. These findings provide proof-of-concept evidence that dual targeting of oxidative stress and complement activation protects against NaIO3-induced retinal degeneration, supporting further evaluation of this approach in complementary chronic models.