Molecular mechanisms limiting the AAV gene therapy treatment window in mouse models of blue cone monochromacy.

ABSTRACT: Blue cone monochromacy (BCM) is a severe X-linked blinding disorder caused by mutations in the OPN1LW/OPN1MW locus, resulting in impaired cone function and structural degeneration. We conduct a comparative analysis of AAV gene therapy in Opn1mw^-/-/Opn1sw^-/- (double knockout, DKO) and Opn1mw^C198R/Opn1sw^-/- (C198R) BCM mouse models to contrast therapeutic outcomes at different stages. We demonstrate the AAV8^Y733F capsid achieves superior rescue compared to AAV5. Both DKO and C198R models show comparable therapeutic outcomes, with efficacy consistently decreasing in older mice. Structural analysis reveals both models display rapid degenerative changes in cone outer and inner segments. We observe age-related reductions in transgene express

SUBMITTER: Brothers BA 

PROVIDER: S-EPMC12644701 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature