Retinal Pigment Epithelium‐Targeting Gene Therapy Corrects Ocular Symptoms in Mouse and Rat Models of Oculocutaneous Albinism Type I

Oculocutaneous albinism (OCA) represents a genetically heterogeneous autosomal recessive condition marked by reduced melanin production in cutaneous and ocular tissues. This disorder primarily arises from mutations in the <i>TYR</i> gene, which encodes tyrosinase-the rate-limiting enzyme in melanogenesis. Such genetic defects lead to impaired or absent tyrosinase activity, consequently causing melanin deficiency. Currently, no curative treatment exists for OCA1. In this study, we investigated the efficacy of AAV vector-based gene therapy in two murine models of OCA1, evaluating its potential as a therapeutic intervention. B6 albino mice were injected with three AAV8 vectors containing distinct promoters at different dosages, among which AAV8.hRPE65p.hTYRco showed the best therapeutic effect at a dose of 1 × 10⁹ GC/eye. This RPE-targeted strategy restored the expression of functional tyrosinase and melanin deposition in the RPE layer. More importantly, the retinal structure and visual function were maintained at nearly normal levels for up to 12 months, with no obvious toxicity. In addition, we demonstrated that the suprachoroidal cavity delivery of AAV8.hRPE65p.hTYRco restored the expression of tyrosinase and relieved ocular dysfunction in Wistar rats for at least 12 months. The results revealed a long-term, effective, safe strategy for treating OCA1.