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Wen-Tao Deng, Jie Li, Ping Zhu, Beau Freedman, W. Clay Smith, Wolfgang Baehr, William W. Hauswirth; Rescue of M-cone Function in Aged Opn1mw−/− Mice, a Model for Late-Stage Blue Cone Monochromacy. Invest. Ophthalmol. Vis. Sci. 2019;60(10):3644-3651. doi: 10.1167/iovs.19-27079.
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Previously we showed that AAV5-mediated expression of either human M- or L-opsin promoted regrowth of cone outer segments and rescued M-cone function in the treated M-opsin knockout (Opn1mw−/−) dorsal retina. In this study, we determined cone viability and window of treatability in aged Opn1mw−/− mice.
Cone viability was assessed with antibody against cone arrestin and peanut agglutinin (PNA) staining. The rate of cone degeneration in Opn1mw−/− mice was quantified by PNA staining. AAV5 vector expressing human L-opsin was injected subretinally into one eye of Opn1mw−/− mice at 1, 7, and 15 months old, while the contralateral eyes served as controls. M-cone–mediated retinal function was analyzed 2 and 13 months postinjection by full-field ERG. L-opsin transgene expression and cone outer segment structure were examined by immunohistochemistry.
We showed that dorsal M-opsin dominant cones exhibit outer segment degeneration at an early age in Opn1mw−/− mice, whereas ventral S-opsin dominant cones were normal. The remaining M-opsin dominant cones remained viable for at least 15 months, albeit having shortened or no outer segments. We also showed that AAV5-mediated expression of human L-opsin was still able to rescue function and outer segment structure in the remaining M-opsin dominant cones when treatment was initiated at 15 months of age.
Our results showing that the remaining M-opsin dominant cones in aged Opn1mw−/− mice can still be rescued by gene therapy is helpful for establishing the window of treatability in future blue cone monochromacy clinical trials.
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