Gene therapy for diabetic retinopathy

Diabetic retinopathy (DR) remains a major cause of preventable vision loss worldwide. Intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is first-line for vision-threatening diabetic macular edema (DME) and is effective in randomized trials; however, it requires repeated injections and intensive follow-up, which are difficult to sustain in routine practice, contributing to lower treatment intensity and more modest real-world outcomes. In parallel, DR is increasingly framed as a tissue-specific neurovascular complication: Diabetes disrupts the retinal neurovascular unit and the blood-retinal barrier through interrelated mechanisms, including oxidative stress, advanced glycation end products, inflammatory signaling, and VEGF-driven vascular permeability and neovascularization. These features motivate longer-acting, mechanism-informed approaches. Ocular gene transfer has become a credible translational strategy, supported by clinical precedents in inherited retinal disease and by “retinal biofactory” programs in neovascular age-related macular degeneration, demonstrating sustained intraocular expression of anti-angiogenic effectors with a reduced need for supplemental injections in selected settings. Building on these foundations, DR/DME gene-therapy development is largely centered on durable intraocular anti-VEGF activity delivered via intravitreal, subretinal, or suprachoroidal routes. At the same time, next-generation concepts extend toward modulation of inflammation, vascular stabilization, and neurovascular protection based on preclinical evidence. This review synthesizes the mechanistic rationale, translational data, and emerging clinical experience in DR/DME. It critically discusses key constraints - including intraocular inflammation risk, route, and dose-dependent tolerability, patient selection, and the long-term durability and control of transgene expression - positioning gene therapy as a potential evolutionary complement to current care rather than a simple replacement.