PERSPECTIVES Gene Therapy for PRPH2-Associated Ocular Disease: Challenges and Prospects

The peripherin-2 (PRPH2) gene encodes a photoreceptor-specific tetraspanin protein called peripherin-2/retinal degeneration slow (RDS), which is critical for the formation and maintenance of rod and cone outer segments. Over 90 different disease-causing mutations in PRPH2 have been identified, which cause a variety of forms of retinitis pigmentosa and macular degeneration. Given the disease burden associated with PRPH2 mutations, the gene has long been a focus for preclinical gene therapy studies. Adeno-associated viruses and compacted DNA nanoparticles carrying PRPH2 have been successfully used to mediate improvement in the rds–/– and rds+/– mouse models. However, complexities in the pathogenic mechanism for PRPH2-associated macular disease coupled with the need for a precise dose of peripherin-2 to combat a severe haploinsufficiency phenotype have delayed the development of clinically viable genetic treatments. Here we discuss the progress and prospects for PRPH2-associated gene therapy.
Source: Cold Spring Harbor perspectives in medicine - Category: Research Authors: Tags: Retinal Disorders: Genetic Approaches to Diagnosis and Treatment PERSPECTIVES Source Type: research

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Source: Human Gene Therapy - Category: Genetics & Stem Cells Authors: Source Type: research
Authors: Petersen-Jones SM, Occelli LM, Biel M, Michalakis S Abstract Mutations in the gene encoding the phosphodiesterase 6 alpha subunit (PDE6A) account for 3-4% of autosomal recessive retinitis pigmentosa (RP), and currently no treatment is available. There are four animal models for PDE6A-RP: a dog with a frameshift truncating mutation (p.Asn616ThrfsTer39) and three mouse models with missense mutations (Val685Met, Asp562Trp, and Asp670Gly) showing a range of phenotype severities. Initial proof-of-concept gene augmentation studies in the Asp670Gly mouse model and dog model used a subretinally delivered adeno-ass...
Source: Advances in Experimental Medicine and Biology - Category: Research Tags: Adv Exp Med Biol Source Type: research
X-linked retinoschisis (XLRS) is an inherited ocular disease caused by mutations in the RS1 gene which results in the abnormal splitting of the retinal layers. It is the leading cause of macular degeneration in males, and approximately 1:15,000 individuals in the US are affected by this condition.   XLRS causes progressive vision loss, and affected individuals are unable to perform simple daily activities such as reading, writing and driving. This condition can lead to vitreous hemorrhage and retinal detachment in up to 40% of patients – resulting in total blindness.A current treatment option includes a tissue-s...
Source: NIH OTT Licensing Opportunities - Category: Research Authors: Source Type: research
Abstract Degenerative retinal diseases such as retinitis pigmentosa (RP) and Leber's congenital amaurosis (LCA) may lead to blindness without effective treatment. With the rapid advancement of the CRISPR/Cas9 genome editing technology, in vivo application of CRISPR/Cas9 holds immense potential for treatment of these diseases. Adeno-associated virus (AAV) vectors are an ideal gene transfer tool for delivery of CRISPR components to the retina. Here, we describe a protocol for utilizing an AAV-based CRISPR/Cas9 system for in vivo genome editing in the retina. PMID: 30783971 [PubMed - indexed for MEDLINE]
Source: Mol Biol Cell - Category: Molecular Biology Authors: Tags: Methods Mol Biol Source Type: research
Lorenz B, Stieger K Abstract Genome editing represents a powerful tool to treat inherited disorders. Highly specific endonucleases induce a DNA double strand break near the mutant site, which is subsequently repaired by cellular DNA repair mechanisms that involve the presence of a wild type template DNA. In vivo applications of this strategy are still rare, in part due to the absence of appropriate animal models carrying human disease mutations and knowledge of the efficient targeting of endonucleases. Here we report the generation and characterization of a new mouse model for X-linked retinitis pigmentosa (XLRP) ...
Source: Translational Research : the journal of laboratory and clinical medicine - Category: Laboratory Medicine Authors: Tags: Transl Res Source Type: research
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Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research
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Source: Journal of Cellular Biochemistry - Category: Biochemistry Authors: Tags: Article Source Type: research
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