Efficacy and safety of AAV-mediated gene therapy for choroideremia: a systematic review and meta-analysis.

Abstract

Choroideremia is a rare X-linked inherited retinal dystrophy caused by mutations in the <i>CHM</i> gene, leading to progressive degeneration of the retinal pigment epithelium (RPE), choroid, and photoreceptors. Current management remains largely supportive, and gene therapy has emerged as a potential disease-modifying treatment. This study aimed to systematically evaluate the efficacy and safety of adeno-associated virus (AAV)-mediated gene therapy for choroideremia. A systematic review and meta-analysis were conducted in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 guidelines and registered in International Prospective Register of Systematic Reviews (PROSPERO) (CRD420251146173). Six databases (PubMed, Embase, Scopus, ScienceDirect, Web of Science, and the Cochrane Library) were searched from inception to December 3, 2025. Clinical trials and prospective observational studies evaluating AAV-mediated gene therapy targeting the Rab escort protein 1 (REP1) gene were included. Outcomes included best-corrected visual acuity (BCVA), retinal sensitivity measured by microperimetry, preserved RPE area on fundus autofluorescence (FAF), subfoveal choroidal thickness, and treatment-emergent adverse events (TEAEs). Random-effects meta-analyses were performed using Comprehensive Meta-Analysis software. Eleven clinical studies involving 308 participants were included. Gene therapy demonstrated a significant improvement in retinal sensitivity (mean difference [MD] 0.78 dB, 95% CI: 0.58-0.99, p < 0.001) with consistent effects across follow-up durations up to 48 months. BCVA showed a significant pooled improvement of 3.07 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (95% CI: 1.85-4.30, p < 0.001), with greater gains observed at 24 months. Structural outcomes indicated reduced RPE degeneration (MD -4.41, 95% CI: -6.39 to -2.44, p < 0.001) and increased subfoveal choroidal thickness (MD 9.13 μm, 95% CI: 7.53-10.72, p < 0.001). TEAEs occurred in approximately 35% of treated participants in the pooled event-rate analysis, with the majority of events being mild to moderate and procedure-related, and a relatively low incidence of serious adverse events (<20%). AAV-mediated gene therapy for choroideremia demonstrates modest functional benefits and structural preservation signals. TEAEs are relatively common and are predominantly procedure-associated ocular events, although most reported events are mild to moderate and serious complications remain uncommon. The therapy appears to act primarily as a disease-modifying intervention that stabilizes retinal degeneration rather than restoring vision, supporting further trials with earlier intervention, optimized delivery strategies, and longer follow-up. No specific funding was received from any funding bodies in the public, commercial, or not-for-profit sectors.