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Published on: November 19, 2011
Gene therapy in the rd6 mouse model of retinal degeneration
Astra Dinculescu1, Seok-Hong Min, Wen-Tao Deng
1Department of Ophthalmology, College of Medicine, University of Florida, 1600 SW Archer Road, 32610, Gainesville, FL, USA, astra@ufl.edu.
Abstract:
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 β-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.
Insights
Gene therapy using a novel AAV2 vector slowed photoreceptor degeneration in rd6 mice with retinitis pigmentosa. However, functional recovery was minimal, suggesting AAV8 may be more effective for Mfrp-related RP.
Area of Science:
- Ophthalmology
- Genetics
- Molecular Biology
Background:
- The rd6 mouse is a genetic model for autosomal recessive retinitis pigmentosa (RP) caused by mutations in the membrane-type frizzled related protein (MFRP) gene.
- Previous studies demonstrated that AAV8-mediated delivery of MFRP could prevent photoreceptor cell death and restore retinal function in rd6 mice.
Purpose of the Study:
- To evaluate the efficacy of gene therapy using a quadruple tyrosine-mutant AAV2 vector for treating RP in rd6 mice.
- To assess the impact of MFRP gene therapy on retinal structure and function.
Main Methods:
- Subretinal delivery of a quadruple tyrosine-mutant scAAV2 vector expressing MFRP driven by the smCBA promoter in rd6 mice at postnatal day 14.
- Assessment of photoreceptor degeneration, subretinal cell accumulation, MFRP expression localization, and retinal function via electroretinography.
Main Results:
- Gene therapy significantly slowed photoreceptor degeneration and prevented abnormal subretinal cell accumulation.
- MFRP expression was observed in the retinal pigment epithelium (RPE) apical membrane, microvilli, and photoreceptor inner segments.
- Despite structural preservation, gene therapy showed minimal improvement in retinal function.
Conclusions:
- The quadruple tyrosine-mutant scAAV2 vector demonstrates potential in slowing RP progression by preserving retinal structure.
- The limited functional recovery suggests that the scAAV8 (Y733F) vector might be more efficient for treating Mfrp-associated RP.
