Efficacy and Safety of Gene Therapy for Neovascular Age-Related Macular Degeneration: A Systematic Review and Meta-Analysis.

Abstract

This systematic review and meta-analysis evaluated whether gene therapy provides safe and clinically meaningful efficacy for patients with neovascular age-related macular degeneration (nAMD). The clinical question addressed outcomes in patients with nAMD receiving gene therapy (primarily adeno-associated virus-based anti-vascular endothelial growth factor (anti-VEGF) constructs) compared with baseline or standard care contexts, focusing on visual acuity, anatomical response, treatment burden, and safety. Anti-VEGF intravitreal injections remain the current standard of care but require frequent administration and long-term adherence. nAMD is a major cause of irreversible vision loss in older adults and imposes substantial treatment burden due to repeated injections. Gene therapy aims to achieve sustained intraocular therapeutic protein expression after a single or infrequent administration, potentially reducing injection frequency while maintaining disease control. Establishing safety and functional efficacy is critical before translation into routine retinal practice. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, databases (PubMed, Embase, Scopus, Web of Science, Google Scholar, and Cochrane Library) were searched from inception to February 1, 2026. Eligible studies were prospective interventional clinical studies evaluating gene therapy in neovascular age-related macular degeneration, including randomized early-phase trials and open-label dose-escalation cohorts. Primary outcomes included best-corrected visual acuity (BCVA), central subfield thickness (CST), rescue anti-VEGF requirement, mortality, and adverse events (AEs). Risk of bias was assessed using the revised Cochrane Risk of Bias tool version 2 (RoB 2) and Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tools. Multilevel random-effects meta-analyses using restricted maximum likelihood (REML) accounted for clustering of multiarm cohorts. Eight prospective interventional studies comprising 203 treated participants were included, including randomized early-phase trials and open-label dose-escalation cohorts. The primary multilevel REML analysis showed no significant pooled BCVA improvement (mean difference (MD) 0.54 Early Treatment Diabetic Retinopathy Study (ETDRS) letters; 95% confidence interval (CI), -7.38 to 8.46), despite favorable fixed-effect sensitivity estimates. CST demonstrated significant anatomical reduction (MD 37.13 µm; 95% CI, 26.63-47.62). Approximately 44% of treated eyes required rescue anti-VEGF injections. Safety outcomes showed low-to-moderate cumulative event probabilities, although estimates varied by model, endpoint, and vector platform. Publication bias was detected for BCVA and CST but was minimal for most safety outcomes. Gene therapy for neovascular age-related macular degeneration demonstrates encouraging anatomical efficacy and manageable short- to midterm safety signals but lacks consistent functional visual improvement. Current evidence supports a treatment-burden-reducing adjunctive role rather than replacement of conventional anti-VEGF therapy. Evidence strength is limited by early-phase designs, small sample sizes, and clinical heterogeneity; ongoing phase 3 trials are required to define long-term efficacy and clinical positioning.