This project is focused on accelerating the development and pre-clinical testing of new and effective approaches to therapy of hereditary retinal degenerations. These diseases are a major cause of blindness in people, affecting over 100,000 Americans, and are caused by a large number of different gene mutations, not all of which have yet been identified. Similar diseases also affect dogs, in many cases caused by identical or essentially similar gene mutations to those affecting people. In this project, studies will be undertaken in a research colony of dogs affected by such hereditary retinal diseases to better understand the genetic and pathogenetic mechanisms of these diseases, and evaluate potential methods of disease prevention, therapy or amelioration. Specific canine strains with well characterized retinal disorders will be maintained, bred, and made available to research investigators for collaborative studies aimed at a) increasing our understanding of the molecular mechanisms involved in these diseases and b) preclinical evaluation of potential therapies. Collaborations to effectively utilize these mutants will be initiated by the Principal Investigators interacting with independently funded investigators, to develop, implement and conduct specific protocols for optimal utilization of these mutants. Special emphasis will be placed on collaborative studies that: i) develop vectors for gene therapy that primarily target rod and/or cone photoreceptors, and test these vectors in appropriate canine models. For example, cone-specific vectors will be tested in canine models of achromatopsia, and rod-specific vectors will be tested in a canine model of autosomal dominant retinitis pigmentosa. ii) identify the causative mutations in new canine hereditary retinal degenerations, and investigate the cell biologic mechanisms critical to the pathogenesis of such diseases. For example, the mutations responsible for 3 canine cone-rod dystrophies will be identified. This will then allow these models to be used for gene-specific therapy studies. iii) Identify molecular signals favoring either the death or survival of photoreceptors during the onset of disease, and attempt to modulate such processes as either an adjunct or alternative to gene-specific therapies.

Public Health Relevance

Hereditary retinal degenerations are a major cause of human blindness. Before potential therapies can be made available for affected people it is essential that they be tested for effectiveness and evaluated for safety in appropriate clinically relevant model systems. This research proposal focuses on the development and preclinical proof of principle testing of new gene therapies to restore retinal function and prevent degeneration in genetically affected retinas.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Study Section
Special Emphasis Panel (ZRG1-CB-G (02))
Program Officer
Shen, Grace L
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University of Pennsylvania
Other Clinical Sciences
Schools of Veterinary Medicine
United States
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Gardiner, Kristin L; Downs, Louise; Berta-Antalics, Agnes I et al. (2016) Photoreceptor proliferation and dysregulation of cell cycle genes in early onset inherited retinal degenerations. BMC Genomics 17:221
Appelbaum, Tatyana; Becker, Doreen; Santana, Evelyn et al. (2016) Molecular studies of phenotype variation in canine RPGR-XLPRA1. Mol Vis 22:319-31
Iwabe, Simone; Ying, Gui-Shuang; Aguirre, Gustavo D et al. (2016) Assessment of visual function and retinal structure following acute light exposure in the light sensitive T4R rhodopsin mutant dog. Exp Eye Res 146:341-53
Downs, Louise M; Aguirre, Gustavo D (2016) FAM161A and TTC8 are Differentially Expressed in Non-Allelelic Early Onset Retinal Degeneration. Adv Exp Med Biol 854:201-7
Cideciyan, Artur V; Roman, Alejandro J; Jacobson, Samuel G et al. (2016) Developing an Outcome Measure With High Luminance for Optogenetics Treatment of Severe Retinal Degenerations and for Gene Therapy of Cone Diseases. Invest Ophthalmol Vis Sci 57:3211-21
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Kondo, Mineo; Das, Gautami; Imai, Ryoetsu et al. (2015) A Naturally Occurring Canine Model of Autosomal Recessive Congenital Stationary Night Blindness. PLoS One 10:e0137072
Marsili, Stefania; Genini, Sem; Sudharsan, Raghavi et al. (2015) Exclusion of the unfolded protein response in light-induced retinal degeneration in the canine T4R RHO model of autosomal dominant retinitis pigmentosa. PLoS One 10:e0115723

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