Can Gene Therapy Transform the Treatment Landscape of Posterior Segment Eye Diseases? A Comprehensive Review of Recent Advancements

Posterior segment eye diseases (PSEDs) encompass a diverse group of conditions affecting the retina, choroid, optic nerve, and vitreous humor, often leading to progressive and irreversible vision loss. Age-related macular degeneration (AMD), diabetic retinopathy (DR), retinitis pigmentosa (RP), and inherited retinal diseases (IRDs) are among the most clinically significant PSEDs with a substantial global burden and economic impact. Conventional treatments for PSEDs have limitations that necessitate the development of novel therapies that address the underlying molecular drivers of the disease. Gene therapy has emerged as a promising approach, offering the potential for durable and curative outcomes through precise genetic manipulation. Advancements in gene therapy strategies, including gene augmentation, gene editing, RNA-based therapies, and optogenetics, have led to significant progress in preclinical studies and clinical trials across various PSED subtypes. US Food and Drug Administration (FDA) approval of voretigene neparvovec (Luxturna®) for RPE65-associated IRDs validated the clinical viability of ocular gene therapy, while ongoing trials for AMD, DR, and other IRDs continue to expand the therapeutic landscape. Innovations in viral and non-viral delivery systems, such as dual AAV vectors, lipid nanoparticles, and novel biomaterials, have enhanced the efficiency and specificity of gene delivery to the retina. However, challenges persist, including immune responses to viral vectors, limited transduction efficiency in certain cell types, and anatomical barriers posed by the blood–retinal barrier. Future directions in ocular gene therapy include the development of precision genome editing techniques, such as prime editing, miRNA-based regulation, and combinatorial approaches integrating gene therapy with stem cell transplantation or neuroprotective agents. As the field continues to evolve, addressing these challenges and optimizing gene therapy strategies will be crucial in translating the transformative potential of ocular gene therapy into clinical reality for patients with PSEDs.