Gene Therapy for nAMD Doesn’t Replace Anti-VEGF, Meta-Analysis Shows

Challenging expectations that gene therapy might replace conventional anti-VEGF regimens, current evidence suggests the intervention acts as an adjunctive or treatment-burden-reducing strategy rather than a definitive standalone intervention. Photo: Getty Images; Anna Bedwell, OD. Click image to enlarge. Anti-VEGF injections remain the standard treatment for neovascular age-related macular degeneration (nAMD); yet, the modality demands frequent visits and high costs, while also yielding variable responses. Gene therapy is an emerging alternative to reduce treatment burden, delivering sustained therapeutic protein expression from one-time or infrequent administration. Despite multiple FDA approvals highlighting its promise, important caveats remain: heterogeneity in nAMD may require personalized approaches; immune reactions and off-target effects are possible; long-term durability and late adverse events need study; and high manufacturing costs and technical complexity raise access and implementation concerns. A new systematic review and meta-analysis in American Journal of Ophthalmology evaluated the current research on ocular gene therapy approaches for nAMD to determine whether the modality delivers clinically meaningful benefits—beyond reducing treatment burden—while maintaining acceptable safety. They reported that while gene therapy shows encouraging anatomic effects and generally manageable safety, it has not yet translated into consistent functional (visual acuity) gains, supporting an adjunctive rather than replacement role for anti-VEGF therapy at this stage.To conduct the study, the researchers scoured multiple databases for prospective interventional clinical trials evaluating gene therapy in nAMD, identifying eight—seven randomized and one non-randomized—comprising a total of 203 treated patients. Primary outcomes included best-corrected visual acuity (BCVA), central subfield thickness (CST), rescue anti-VEGF requirement, mortality and adverse events.The results demonstrated no significant pooled BCVA improvement (mean deviation [MD]: 0.54 letters) despite favorable fixed-effect estimates. CST, on the other hand, showed significant anatomical reduction (MD: 37.13µm).A considerable number of eyes—approximately 44%—required rescue anti-VEGF injections, which the researchers noted in their paper “indicates that current gene therapy approaches do not yet achieve sufficient disease control as monotherapy.” This finding, they argued, “challenges early expectations that gene therapy could function as a standalone replacement for anti-VEGF therapy and underscores its present role as an adjunctive strategy as a treatment-burden-reducing approach.”The pooled trial data did reflect a promising safety profile, with safety outcomes showing generally low-to-moderate event probabilities, as follows: mortality (~8%), serious adverse events (21% to 38%), inflammation (~20%) and retinal hemorrhage (~12%). The study authors wrote, “The aggregated rates of adverse events were generally within acceptable limits, with controllable inflammation, changes in retinal pigmentation and decreased visual acuity being the most frequently observed occurrences.” Importantly, fatality rates were not associated with the treatment, and mild inflammation and subconjunctival hemorrhage typically resolved without long-term consequences.While these findings are encouraging overall, the researchers pointed out that there was noticeable heterogeneity in outcomes stemming from variance in administration techniques (subretinal vs. intravitreal), vector doses and patients' initial conditions. “These disparities highlight the need to refine delivery methods and establish standardized protocols to ensure consistent results,” they wrote.In summary, while these findings suggest gene therapy cannot serve as a standalone intervention for nAMD at this time, “the observed 80% to 98% reduction in rescue anti-VEGF injection frequency in selected trials may translate into substantially fewer clinic visits and invasive procedures, which are known contributors to treatment fatigue and non-adherence in nAMD.” These benefits “suggest meaningful quality-of-life gains if sustained in late-phase trials,” they concluded.Click here for the journal source. Chen KY, Chan HC, Chan C-M. Can gene therapy revolutionize treatment of neovascular age-related macular degeneration. Am J Ophthalmol. April 4, 2026. [Epub ahead of print]. This article was developed by the editorial staff in conjunction with experts in the field. In the process, AI may have been among the editorial tools used to meet the goals of human editors, who approved all content.