**Background:** Age-related macular degeneration (AMD) is a leading cause of vision loss in aging populations. Wet (neovascular) AMD, though less common than dry AMD, accounts for approximately 90% of AMD-related sight loss. Current standard therapy involves repeated intravitreal injections of anti-VEGF antibodies (e.g., aflibercept, ranibizumab) every 8–12 weeks after three monthly loading doses. While effective in halting disease progression, this regimen imposes a significant burden on patients due to frequent clinic visits, high costs, and potential side effects. Gene therapy offers a paradigm shift by enabling sustained endogenous production of anti-VEGF proteins after a single administration, potentially eliminating the need for lifelong injections. This narrative review updates information on completed and ongoing clinical trials of gene therapy for wet AMD, with a focus on AAV-based vectors and emerging genome editing approaches.
**Methods:** The authors conducted a narrative/perspective review, summarizing data from ClinicalTrials.gov (accessed January 2024) and published literature. They identified 22 studies on gene therapy in wet AMD, including one completed with results, four completed, twelve recruiting, three active not recruiting, one not yet recruiting, and one enrolling by invitation. The review provides detailed analysis of two leading clinical trials: ADVM-022 (OPTIC) and RGX-314, as well as brief discussion of genome editing strategies.
**Key Results:**
- **ADVM-022 (ixo-vec):** Phase I open-label trial using AAV2.7m8 capsid encoding aflibercept cDNA. High-dose group showed a 98% decrease in anti-VEGF injections required; low-dose group showed an 80% reduction. Best-corrected visual acuity (BCVA) remained stable over 2 years. Mean central subfield thickness decreased and remained stable. Ocular treatment-emergent adverse events (TEAEs) were mild to moderate (anterior chamber cells, vitreal cells). Five serious TEAEs occurred (cataract, dry AMD, retinal detachment, recurrent uveitis), but dry AMD and uveitis were not attributed to ixo-vec.
- **RGX-314 (ABBV-RGX-314):** Uses AAV8 vector encoding a ranibizumab-like Fab fragment. Phase I/IIa subretinal delivery was well-tolerated with no abnormal immune response or ocular inflammation. Phase II subretinal study (BRX vs. HS processes) showed similar clinical profiles; 73% of subjects were injection-free at 6 months. BCVA improved by 3–8 letters. Five SAEs in four patients, none drug-related. Phase II suprachoroidal delivery (AAVIATE) showed 15 SAEs, none drug-related; BCVA worsened compared with monthly ranibizumab.
- **Genome editing:** Preclinical studies using CRISPR/Cas9 to knockout VEGFA in a laser-induced CNV mouse model showed a 45% reduction in CNV area (vs. 39% with aflibercept), with long-lasting effect after single injection. Clinical trial NCT06031727 (SIGHT-I) is investigating CRISPR/Cas13-mediated RNA targeting for wet AMD.
**Clinical Implications:** Gene therapy for wet AMD represents a major advance by potentially converting a lifetime of repeated injections into a single in-office procedure. The ADVM-022 and RGX-314 trials demonstrate that sustained intraocular anti-VEGF production is achievable, with most patients requiring no or fewer supplemental injections. However, several limitations remain: small sample sizes, unmasked designs, lack of comparison to untreated controls, and safety concerns including inflammation and rare serious adverse events. The durability of expression beyond 2–3 years is unknown. Importantly, these therapies target the downstream angiogenic effects of VEGF rather than the underlying AMD pathology (e.g., RPE dysfunction, complement dysregulation). Future directions include optimizing AAV vectors (tropism, packaging capacity, immune evasion), exploring suprachoroidal delivery, and enrolling treatment-naive patients to better assess efficacy. Genome editing offers potential for more precise and durable modulation of angiogenic pathways, but clinical data are lacking. The authors estimate that if Phase 3 trials confirm Phase 1/2 results, a 'one-and-done' gene therapy for wet AMD could be available in 3–4 years.