Preclinical evaluation of NG101, a potential AAV gene therapy for wet age-related macular degeneration.

Age-related macular degeneration (AMD) is a leading cause of vision loss in individuals over the age of 55. Approximately 10%-15% of AMD patients develop choroidal neovascularization (CNV), leading to wet AMD (wAMD), which accounts for nearly 90% of AMD-related blindness. Inhibition of vascular endothelial growth factor (VEGF) is the standard treatment for wAMD. However, the frequent administration of the current treatment imposes a significant burden on wAMD patients. Therefore, there is an unmet need for treatments that require less-frequent administration. Here, we present findings on the safety and efficacy of NG101, a recombinant adeno-associated virus (rAAV) vector encoding aflibercept, an anti-VEGF agent, for wAMD therapy. A single subretinal injection of NG101 effectively reduced CNV lesion leakage and size at doses as low as 1 × 10 in mouse and 3 × 10 viral genomes per eye in cynomolgus monkeys. In cynomolgus monkeys, NG101-derived aflibercept expression in ocular tissues persisted for 1 year post-injection, indicating sustained therapeutic potential. Biodistribution analysis revealed that NG101 was primarily localized in ocular tissues. Only mild and transient ocular inflammatory responses were observed. Overall, these findings suggest that NG101, with its efficacy at low doses and sustained expression, is a promising therapeutic candidate for wAMD.