New AAV gene therapy reverses age-related macular degeneration

Neovascular age-related macular degeneration (nAMD) is a progressive eye disease characterized by choroidal neovascularization and subretinal hemorrhage and exudation, leading to vision impairment. Current first-line treatment for nAMD are anti-VEGF agents, which has shown promising therapeutics outcomes.

Despite their efficacy, the anti-VEGF therapies require frequent intravitreal (IVT) injections and regular clinic visits to sustain their benefits, bringing significant challenges for long-term patient compliance and real-world effectiveness. As such, emerging long-term therapeutics strategies for nAMD need to be further studied.

Research

A groundbreaking study titled "An Engineered Intravitreal Injection Retinal-Pigment-Epithelium-Tropic Adeno-Associated Virus Vector Expressing a Bispecific Antibody Binding VEGF-A and ANG-2 Rescues Neovascular Age-Related Macular Degeneration in Animal Models and Patients" has unveiled a promising new gene therapy approach for treating nAMD. AAV is a widely used gene delivery tool in ocular gene therapy due to its safety and ability to provide long-term transgene expression in retinal cells.

This research highlights the development of a novel engineered AAV vector (AAV-RPE) as well as a bispecific antibody (VEGF-Ang2) targeting both vascular endothelial growth factor-A (VEGF-A) and angiopoietin-2 (ANG-2), two key drivers of abnormal blood vessel growth and leakage in nAMD. A single intravitreal injection of the AAV gene therapy (XMVA09) contributes to long-term expression of the therapeutic antibody, especially in RPE cells.

Preclinical study demonstrated that XMVA09 can effectively suppress neovascularization and vascular leakage in CNV models in both mice and non-human primates (NHPs). In mouse CNV models, compared to AAV2.7m8-aflibercept (ADVM022), XMVA09, AAV-RPE-aflibercept, and AAV2.7m8-VEGF-Ang2 show a significant advantage in therapeutic efficacy (Fig.1).

NHP studies indicated that the gene therapy is safe with no evidence of retinal toxicity and low immunogenicity. Moreover, an investigator-initiated clinical trial demonstrated that the gene therapy is well-tolerated and of significant clinical benefit in nAMD patients.

Conclusion and future prospects

Collectively, the research represents an innovative gene therapy, which offers a safe and effective treatment option for nAMD. The research team plans to advance to larger clinical trials to confirm safety and efficacy. If successful, this approach could also be adapted for other retinal diseases driven by angiogenesis.