Gene delivery of wild-type rhodopsin rescues retinal function in an autosomal dominant retinitis pigmentosa mouse model.

Autosomal dominant retinitis pigmentosa (ADRP) is frequently caused by mutations within the gene for the opsin of rod photoreceptor cells. Studies on transgenic mice, carrying mutated rhodopsin () transgene on different genetic backgrounds suggested that that an increased amount of wild-type in ADRP photoreceptors attenuated the impact of the mutant transgene. Therefore, we employed a gene therapy approach with a help of Adeno-associated virus (AAV) to treat mice expressing a P23H mutant human transgene. Knowing that AAV5 primarily transduces photoreceptor cells, we designed “hardened” form of the rhodopsin gene () that expressed normal rhodopsin and was specifically resistant to degradation by the previously tested siRNA301. AAV5 was subretinaly injected into the right eyes of P23H RHO mice at post-natal day 15. Animals were analyzed monthly by electroretinography (ERG) for 6 months. Analysis of the full field scotopic electroretinogram (ERG) demonstrated that increased expression of slowed the rate of retinal degeneration in P23H mice with increased amplitudes in both a-wave and b-wave amplitudes compared to control eyes. An increase in the ERG amplitudes was correlated with improvement of retinal structure. The thickness of the outer nuclear layer in AAV-RHO301 injected eyes was increased by 80% compared to control eyes. This finding indicates that wild -type could rescue the retinal degeneration in transgenic mice carrying a dominant RHO mutation and that increased production of normal rhodopsin could suppress the effect of the mutant protein. These findings suggest that wild-type can used as a therapeutic agent to retard retinal degeneration in ADRP caused by different mutations of via increased production of normal rhodopsin protein.