Gene Therapy in Opn1mw−/−/Opn1sw−/− Mice and Implications for Blue Cone Monochromacy Patients with Deletion Mutations
| Autor: | Xiajie Ma, Emily R. Sechrest, Diego Fajardo, Ping Zhu, Frank Dyka, Yixiao Wang, Ekaterina Lobanova, Shannon E. Boye, Wolfgang Baehr, Wen-Tao Deng |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Hum Gene Ther |
| ISSN: | 1557-7422 1043-0342 |
| DOI: | 10.1089/hum.2021.298 |
| Popis: | Blue cone monochromacy (BCM) is a congenital vision disorder affecting both middle-wavelength (M) and long-wavelength (L) cone photoreceptors of the human retina. BCM results from abolished expression of green and red light-sensitive visual pigments expressed in M- and L-cones, respectively. Previously, we showed that gene augmentation therapy to deliver either human L- or M-opsin rescues dorsal M-opsin dominant cone photoreceptors structurally and functionally in treated M-opsin knockout (Opn1mw(−/−)) mice. Although Opn1mw(−/−) mice represent a disease model for BCM patients with deletion mutations, at the cellular level, dorsal cones of Opn1mw(−/−) mice still express low levels of S-opsin, which are different from L- and M-cones of BCM patients carrying a congenital opsin deletion. To determine whether BCM cones lacking complete opsin expression from birth would benefit from AAV-mediated gene therapy, we evaluated the outcome of gene therapy, and determined the therapeutic window and longevity of rescue in a mouse model lacking both M- and S-opsin (Opn1mw(−/−)/Opn1sw(−/−)). Our data show that cones of Opn1mw(−/−)/Opn1sw(−/−) mice are viable at younger ages but undergo rapid degeneration. AAV-mediated expression of human L-opsin promoted cone outer segment regeneration and rescued cone-mediated function when mice were injected subretinally at 2 months of age or younger. Cone-mediated function and visually guided behavior were maintained for at least 8 months post-treatment. However, when mice were treated at 5 and 7 months of age, the chance and effectiveness of rescue was significantly reduced, although cones were still present in the retina. Crossing Opn1mw(−/−)/Opn1sw(−/−) mice with proteasomal activity reporter mice (Ub(G76V)–GFP) did not reveal GFP accumulation in Opn1mw(−/−)/Opn1sw(−/−) cones eliminating impaired degradation of ubiquitinated proteins as stress factor contributing to cone loss. Our results demonstrate that AAV-mediated gene augmentation therapy can rescue cone structure and function in a mouse model with a congenital opsin deletion, but also emphasize the importance that early intervention is crucial for successful therapy. |
| Databáze: | OpenAIRE |
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