Retinal BMI1 Expression Preserves Photoreceptors in Sodium-Iodate-Induced Oxidative Stress Models

Dry age-related macular degeneration (AMD) is a leading cause of vision loss in individuals over 50, yet no approved therapies exist for early or intermediate stages of the disease. Oxidative stress is a central driver of retinal degeneration in AMD, and sodium iodate (NaIO₃)-induced injury serves as a well-characterized model of oxidative damage to the retinal pigment epithelium (RPE) and photoreceptors. BMI1, a poly-comb group protein involved in DNA repair, mitochondrial function, and cellular renewal, has emerged as a promising therapeutic target for retinal neuroprotection. We evaluated the efficacy of AAV-mediated BMI1 gene delivery in murine models using two administration routes: subretinal (SR) and suprachoroidal (SC). AAV5.BMI1 (1 × 10⁹ vg/eye) was delivered SR in Balb/c mice and evaluated at 4 and 15 weeks post-injection. AAV8.BMI1 (5 × 10⁹ or 1 × 10¹⁰ vg/eye) was administered SC in C57BL/6 mice and assessed at 4 weeks. Control groups received BSS or AAV8.stuffer. Following NaIO₃ exposure, retinal structure and function were analyzed by optical coherence tomography (OCT), electroretinography (ERG), histology, and molecular assays. SC delivery of AAV8.BMI1 achieved the highest levels of retinal BMI1 expression with no evidence of local or systemic toxicity. Treated eyes showed dose-dependent preservation of outer nuclear layer (ONL) thickness and significantly improved ERG responses indicating structural and functional protection. These findings support SC AAV.BMI1 gene therapy as a promising, minimally invasive, and translatable approach for early intervention in intermediate AMD.