Safety and Efficacy of cceAAV-aflibercept-Fc-YTE (F-CRG-B191): A Gene Therapy for Neovascular Age-Related Macular Degeneration.

Purpose: To evaluate the safety and efficacy of a novel gene therapy vector, covalently closed-end double-stranded adeno-associated virus-aflibercept-Fc-YTE (cceAAV-aflibercept-Fc-YTE; clinical trial name F-CRG-B191), designed for sustained anti-vascular endothelial growth factor (VEGF) expression in the treatment of neovascular age-related macular degeneration (nAMD). Methods: We developed cceAAV-aflibercept-Fc-YTE. The therapeutic efficacy of cceAAV-aflibercept-Fc-YTE was evaluated in both mice and non-human primate (NHP) models with laser-induced choroidal neovascularization (CNV). The incidence of grade IV CNV lesions was quantified. A first-in-human administration of F-CRG-B191 was conducted to assess anatomical and functional outcomes, as well as safety. Immune responses and retinal toxicity were monitored in NHPs and the patient post-injection. Results: Compared to conventional AAV vectors expressing aflibercept, cceAAV-aflibercept-Fc-YTE significantly reduced the incidence of grade IV CNV lesions in both mice and NHP models. In the human subject, F-CRG-B191 administration led to a sustained reduction in CNV area and improvement in visual acuity. No significant immune response or retinal toxicity was observed in either preclinical models or the treated patient. Conclusions: cceAAV-aflibercept-Fc-YTE (F-CRG-B191) is a promising gene therapy candidate for nAMD, demonstrating potent anti-VEGF efficacy, durable therapeutic effects, and favorable safety profiles in both preclinical and early clinical settings.