**Background:** Retinal gene therapy has been a focus of research since the 1990s, with the retina offering advantages such as immune privilege, small size, and easy monitoring. The first FDA-approved gene therapy for an inherited disorder, Luxturna (voretigene neparvovec-rzyl), was approved in 2017 for Leber congenital amaurosis (LCA) type 2 caused by biallelic RPE65 mutations. Despite this milestone, no other ocular gene therapies have been approved in the US, and challenges remain including immunogenicity, targeting, and manufacturing scalability. This review provides a comprehensive overview of the history, approaches, delivery methods, challenges, and future directions of retinal gene therapy.
**Methods:** The authors conducted a narrative review of the literature, covering the history of gene therapy development for retinal diseases, various gene therapy approaches (gene replacement, silencing, editing, and modifier therapy), delivery vectors (viral and non-viral), routes of administration (noninvasive and invasive), and challenges such as identification of disease-causing genes, gain-of-function mutations, effective targeting, immunogenicity, animal model selection, and manufacturing. The review also summarizes ongoing clinical trials for retinal diseases, including more than 30 active studies in the US.
**Key Results:** The review identifies four main gene therapy approaches: gene replacement (e.g., Luxturna for RPE65 mutations), gene silencing (e.g., siRNA targeting VEGF for AMD), gene editing (e.g., CRISPR/Cas9 for CEP290 mutations in LCA10), and modifier gene therapy (e.g., OCU400 for retinitis pigmentosa). Viral vectors, particularly adeno-associated viruses (AAVs), are most commonly used, with serotypes AAV1, 2, 4, 5, 6, 7, 8, and 9 showing retinal tropism. Non-viral vectors include naked DNA/RNA, lipid nanoparticles, and polymers. Routes of administration include subretinal (e.g., Luxturna), intravitreal (e.g., anti-VEGF therapies), and suprachoroidal injections. Challenges include immunogenicity, with neutralizing antibodies and cell-based immune responses observed at doses above 1 × 10^11 vg. The review lists over 30 active clinical trials for conditions such as achromatopsia, age-related macular degeneration (AMD), choroideremia, diabetic macular edema, LCA, Leber hereditary optic neuropathy, retinitis pigmentosa, X-linked retinitis pigmentosa, X-linked retinoschisis, and Stargardt disease. Notable trials include EDIT-101 (CRISPR/Cas9 for LCA10), OCU400 (modifier therapy for RP), and RGX-314 (AAV8 for wet AMD).
**Clinical Implications:** The review emphasizes that while gene replacement therapy is effective for monogenic recessive disorders, it is limited by the need for a known genetic diagnosis and high cost. Mutation-agnostic approaches like modifier gene therapy and optogenetics offer potential for treating patients without a genetic diagnosis or with multiple mutations. Immunogenicity remains a major barrier, with strategies such as co-treatment with corticosteroids, IgG-cleaving endopeptidases, and vector engineering being explored to reduce immune responses. Manufacturing challenges, including scalability and purity of AAV vectors, are being addressed through new technologies like droplet digital PCR (ddPCR) and plasmid-free production systems. The success of Luxturna demonstrates the feasibility of retinal gene therapy, but further improvements in safety, efficacy, and accessibility are needed to expand treatment options for the thousands of patients worldwide with inherited retinal diseases.