AAV Gene Therapy Advances for Neovascular AMD and Inherited Retinal Diseases

Adeno-associated virus (AAV)-based gene therapy offers sustained intraocular delivery of anti-angiogenic agents with a single treatment for neovascular age-related macular degeneration, potentially overcoming the burden of frequent injections required by current therapies. Leading clinical candidates include RGX-314, ADVM-022, 4D-150, and NG101.

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. Globally, it is estimated that approximately 8.69% of individuals aged 45-85 years are affected by AMD. While dry AMD accounts for approximately 85-90% of all AMD cases, neovascular AMD, though less prevalent, is responsible for the majority of severe and rapid vision loss associated with the disease.

The subtype is characterized by the pathological development of choroidal neovascularization (CNV), wherein abnormal blood vessels originating from the choroid penetrate through Bruch's membrane into the subretinal space. These newly formed vessels are leaky and structurally immature, thereby increasing vascular permeability, macular edema, subretinal hemorrhage, and subsequent damage to the photoreceptors and the retinal pigment epithelium. The primary molecular driver of this neovascularization is vascular endothelial growth factor (VEGF), which is upregulated in response to oxidative stress, hypoxia, and retinal inflammation in the aging eye.

Current standard therapy for nAMD involves repeated intravitreal injections of anti-VEGF agents, such as ranibizumab, brolucizumab, aflibercept (targeting VEGF-A, VEGF-B, and placental growth factor) and faricimab (targeting VEGF-A and angiopoietin-2). These biologics act by neutralizing VEGF-A and inhibiting its interaction with VEGF receptors on endothelial cells, thereby suppressing neovascular growth and vascular leakage. While these treatments have significantly improved visual outcomes, they necessitate frequent administration, often monthly or bimonthly, to maintain efficacy. This treatment burden affects both patients and healthcare systems, resulting in poor adherence, incomplete disease suppression, and recurrent disease activity.

AAV vectors have demonstrated exceptional promise due to their ability to transduce non-dividing retinal cells, mediate long-term gene expression, and exhibit minimal immunogenicity in ocular tissues. AAV-mediated expression of anti-VEGF proteins could obviate the need for frequent injections, thereby enhancing treatment adherence and clinical outcomes.

Advances in vector engineering, promoter optimization, and immune modulation are being pursued alongside key challenges such as preexisting immunity and inflammation. Future directions include next-generation capsids, combination regimens, and precision patient selection.

In the broader gene therapy field, multiple approvals across rare genetic disorders have demonstrated that gene therapy can treat disease. Manufacturing bottlenecks, delivery constraints, and costs still limit who can benefit from these advanced treatments. The field is shifting from bespoke, one-off cures toward treatments that can realistically reach patients beyond the rarest of rare diseases.

Many of the first approved liver-directed gene therapies use adeno-associated viral (AAV) vectors, which deliver therapeutic genes that remain episomal rather than integrating into the genome. This approach can produce strong early efficacy, but as liver cells divide and the organ grows, the therapeutic DNA can be progressively diluted, potentially eroding gene expression over time. For pediatric patients, whose livers are still rapidly expanding, this raises fundamental questions about durability, redosing, and whether one-time gene therapies can truly provide permanent benefit.

AAVantgarde Bio is developing gene therapy programs for inherited retinal diseases and working to address transgene size limitations that have constrained AAV vector applications.