AAV-based gene therapies for neovascular AMD

Abstract

Neovascular age-related macular degeneration (nAMD) is a major cause of irreversible vision loss in the elderly, driven by choroidal neovascularization and dysregulated vascular endothelial growth factor (VEGF) signaling. While anti-VEGF injections have transformed management, their frequent administration imposes a substantial burden on patients and limits adherence. Adeno-associated virus (AAV)-based gene therapy offers sustained intraocular delivery of anti-angiogenic agents with a single treatment, potentially overcoming these limitations. This review summarizes the rationale for AAV use in ocular gene therapy, compares major delivery routes, and highlights leading clinical candidates, including RGX-314, ADVM-022, 4D-150, and NG101. Advances in vector engineering, promoter optimization, and immune modulation are discussed alongside key challenges such as preexisting immunity and inflammation. Future directions include next-generation capsids, combination regimens, and precision patient selection. Collectively, these developments position AAV-based gene therapy as a promising strategy to redefine the therapeutic landscape of nAMD.