AAVAnc80L65-CAG-GFP

Adeno-associated viruses (AAVs) are naturally occurring, low-immunogenic viruses that are capable of sustained transgene expression and have been exploited for a variety of successful gene replacement strategies. The field of retinal gene therapy has seen the first approved AAV gene therapy, Luxturna, which targets the retinal pigment epithelium (RPE) and delivers the RPE65 gene to patients with Leber congenital amaurosis via subretinal injection of AAV2 virus. This was followed closely by the second AAV gene therapy approved by the U.S. Food and Drug Administration (FDA), Zolgensma, which is delivered via intravenous injection of AAV9-SMN virus for the treatment of patients with spinal muscular atrophy (SMA). Next-generation vectors are primarily based on capsid modifications of naturally occurring AAVs through two approaches. The first approach, called rational design, involves intentional changes to the viral capsid based on prior knowledge of capsid structure, function, and its effect on tropism. The second approach, called directed evolution, involves the selection of successful random mutations, often followed by preclinical animal studies to determine function and new tropism. Anc80L65 (Anc80) was developed through a form of rational design called ancestral sequence reconstruction and is gaining increasing attention in the field of retinal gene therapy. Anc80 was identified through in silico phylogenetic reconstruction using sequences of a total of 75 AAV serotype isolates and variants and is predicted to be ancestral to AAV 1-3 and 6-9. Anc80 has a higher affinity for the RPE and photoreceptors in mice compared to AAV2 and AAV8. In non-human primates, a higher tropism for the RPE and photoreceptor layers was observed after subretinal injection of Anc80L65 compared to AAV5 and AAV9.