Laterally spreading AAV.SPR enables safe and efficient RS1 delivery to the macula after peripheral subretinal...

Mutations in RS1 are associated with X-linked retinoschisis (XLRS), a common cause of juvenile macular degeneration in males. Schisis cavities in the central retina of these patients have hampered submacular delivery with conventional adeno-associated viruses (AAVs). Clinical trials employing intravitreally injected AAVs showed a lack of efficacy and inflammation. Here, we demonstrate, in non-human primate (NHP) retina, that AAV.SPR, a laterally spreading capsid, transduced photoreceptors in the macula/fovea without the need for central retinal detachment, enabling transgene expression multiple millimeters beyond the subretinal injection (SRI) bleb margins. Peripheral SRI of AAV.SPR-hGRK1-RS1 resulted in robust and properly localized RS1 expression in NHP fovea. Despite being a secreted protein, biodistribution of RS1 remains confined to the area of AAV-RS1 transduction. Having established feasibility for the approach, we performed preclinical proof-of-concept, safety, and efficacy studies in support of "ATSN-201" (NCT05878860). In RS1KO mice, a "hybrid" efficacy/safety study demonstrated dose-dependent improvements in retinal function and structure and proper localization of RS1 following treatment with ATSN-201. A good laboratory practice (GLP) toxicology study in NHPs established safety at the highest dose evaluated. The enhanced transduction and lateral spreading ability of AAV.SPR make it an attractive option for treating inherited retinal diseases including, but not limited to, XLRS.