AI-engineered AAV capsid enables intravitreal delivery for the treatment of diverse retinal degenerations.

Retinal degenerations, including Leber's congenital amaurosis type 1 (LCA1) and wet age-related macular degeneration (wAMD), represent leading causes of vision impairment and blindness, driven by a range of factors, including genetic mutations and pathological neovascularization. While adeno-associated viruses (AAVs) have emerged as a promising platform for sustained gene therapy, most AAVs typically require subretinal injections to reach target cells, which carry risks to retinal integrity. To overcome this limitation, we employed an AI-guided approach to AAV capsid engineering and developed AAV2.PN168, a novel AAV2-derived variant. AAV2.PN168 exhibits extensive retinal transduction via intravitreal injection in both non-human primates and mice. Furthermore, AAV2.PN168 demonstrates high therapeutic efficacy in mouse models both LCA1 and wAMD, respectively. These findings suggest that AAV2.PN168 has translational potential in treating various retinal degenerations, and other ocular diseases requiring efficient, wide-range retinal delivery of therapeutic agents.