Gene therapy for diabetic retinopathy

Abstract

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.

Keywords: Diabetic retinopathy; Diabetic macular edema; Gene therapy; Retinal biofactory; Adeno-associated virus; Suprachoroidal delivery; Inflammation; Neurovascular unit; Genome editing

Core Tip: Gene therapy for diabetic retinopathy is developing as a method to diminish the want for regular intravitreal injections by offering prolonged intraocular modulation of disease pathways. Extensive experience with age-related macular degeneration provides compelling clinical evidence that sustained suppression of pathological vascular signaling is feasible, while preliminary studies on diabetic retinopathy are evaluating the potential for similar durability within the inflammatory diabetic retinal milieu. Significant obstacles to translation encompass delivery- and dose-associated intraocular inflammation, ambiguity concerning long-term efficacy and the practicality of repeated dosage, as well as the necessity for stringent patient selection and monitoring.