The long-term goal of this research is to generate a gene therapy for dominantly inherited forms of retinal disease which lead to blindness.
The aims of this project are designed to develop a treatment for mutations in the RDS/peripherin gene which lead to pattern dystrophy, macular degeneration and autosomal dominant retinitis pigmentosa (ADRP). For this work we will employ mouse models that contain mutations in the RDS/peripherin gene, and we will use Adeno-associated virus to deliver potential therapeutic genes. Because mutations in the RDS/peripherin gene are frequently associated with degeneration of cone photoreceptor cells, we will target the expression of therapeutic genes to cones in addition to rod cells. We have four specific aims: (1) To develop an RNA replacement technology for RDS/peripherin in which levels of endogenous mRNA are reduced using a ribozyme or an siRNA, and a ribozyme- or siRNA-resistant version of the mRNA is supplied simultaneously. (2) To test the gene replacement method in the P216L mouse line that expresses a mutant version of RDS/peripherin leading to ADRP. (3) To develop an AAV- mediated gene targeting method for cone photoreceptor cells, the cells affected by peripherin/rd mutations in pattern dystrophy and macular degeneration. (4) To express the P216L mutation in the context of the NRL knockout mouse, which produces only cone photoreceptors, and to test RNA replacement in this model. Preliminary results from our laboratories and from those of other investigators suggest that these experiments will prove fruitful and will lead to a treatment for retinal diseases caused by RDS mutations. This project is relevant to age-related macular degeneration and retinitis pigmentosa. Age-related macular degeneration (AMD) is the major blinding disease affecting the elderly in developed countries. Some form of AMD affects as many as 1 in 3 people over the age of 70. It leads to scarring and degeneration of the cone-rich central retina, which is required for acute vision, including reading and face-recognition. Retinitis Pigmentosa (RP) affects fewer people, 60,000-100,000 in the US, but it robs them of useful vision at an earlier age. Since many of the mutant genes for RP are known, a gene therapy may be possible for many forms of the disease.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Neuhold, Lisa
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University of Florida
Schools of Medicine
United States
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Petrs-Silva, Hilda; Dinculescu, Astra; Li, Qiuhong et al. (2011) Novel properties of tyrosine-mutant AAV2 vectors in the mouse retina. Mol Ther 19:293-301
Petrs-Silva, Hilda; Dinculescu, Astra; Li, Qiuhong et al. (2009) High-efficiency transduction of the mouse retina by tyrosine-mutant AAV serotype vectors. Mol Ther 17:463-71