Gene Therapy in the Rd6 Mouse Model of Retinal Degeneration

The rd6 mouse is a natural model of an RPE-based (retinal pigment epithelium) autosomal recessive retinitis pigmentosa (RP) caused by mutations in the Mfrp (membrane-type frizzled related protein) gene. Previously, we showed that subretinal delivery of the wild-type mouse Mfrp mediated by a tyrosine-capsid mutant scAAV8 (Y733F) vector prevented photoreceptor cell death, and rescued retinal function as assessed by electroretinography. In this study, we describe the effect of gene therapy on the retinal structure and function in rd6 mice using a quadruple (Y272, 444, 500, 730F) tyrosine-capsid mutant scAAV2 viral vector delivered subretinally at postnatal day 14 (P14). We show that therapy is effective at slowing the photoreceptor degeneration, and in preventing the characteristic accumulation of abnormal phagocytic cells in the subretinal space. MFRP expression as driven by the ubiquitous chicken beta-actin (smCBA) promoter in treated rd6 mice was found predominantly in the RPE apical membrane and the entire length of its microvilli, as well as in the photoreceptor inner segments, suggesting a potential interaction with actin filaments. In spite of preserving retinal morphology, the effects of gene therapy on retinal function were minimal, suggesting that the scAAV8 (Y733F) vector may be more efficient for the treatment of RP caused by Mfrp mutations.