Gene therapy rescues cone function in opn1mw−/−/opn1sw−/−/Nrl−/− mice, an all-cone model of blue cone monochromacy

Blue cone monochromacy (BCM) is a congenital vision disorder caused by the loss of L- and M-cone function, leading to severe loss of visual acuity and color perception deficits. To test gene therapy for BCM in a model that mimics the densely packed foveal cones of human retinas, we generated a triple knockout (TKO) mouse model ( Opn1mw −/− /Opn1sw −/− /Nrl −/− ) with an all-cone retina lacking cone opsins. These mice exhibit abolished cone function, disrupted phototransduction, and altered metabolite profiles resulting from loss of opsin. We then administered AAV-mediated human L-opsin gene supplementation therapy at 1 and 5 months of age to assess cone treatability before and after cone degeneration occurs. Treatment restored cone function, replenished essential cone phototransduction proteins, and partially regenerated some cone outer segment membrane structure. Rescue effects persisted for at least 5 months post-treatment in both younger and older treated groups. These findings demonstrate that opsin-deficient, densely packed cones remain viable targets for gene therapy and support the clinical potential of this approach in BCM patients. This study establishes an all-cone mouse model of blue cone monochromacy and demonstrates that AAV-mediated L-opsin gene therapy rescued cone function and partially regenerated cone outer segment membrane structure. These findings reveal that opsin-deficient cones remain viable targets for treatment, supporting the therapeutic potential of gene replacement in BCM.