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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
7R01EY006855-27
Application #
8389556
Study Section
Special Emphasis Panel (ZRG1-CB-G (02))
Program Officer
Shen, Grace L
Project Start
1992-12-01
Project End
2014-11-30
Budget Start
2013-02-01
Budget End
2013-11-30
Support Year
27
Fiscal Year
2013
Total Cost
$755,360
Indirect Cost
$185,837
Name
University of Pennsylvania
Department
Other Clinical Sciences
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Cooper, Ann E; Ahonen, Saija; Rowlan, Jessica S et al. (2014) A novel form of progressive retinal atrophy in Swedish vallhund dogs. PLoS One 9:e106610
Genini, Sem; Beltran, William A; Stein, Veronika M et al. (2014) Isolation and ex vivo characterization of the immunophenotype and function of microglia/macrophage populations in normal dog retina. Adv Exp Med Biol 801:339-45
Genini, Sem; Guziewicz, Karina E; Beltran, William A et al. (2014) Altered miRNA expression in canine retinas during normal development and in models of retinal degeneration. BMC Genomics 15:172
Beltran, William A; Cideciyan, Artur V; Guziewicz, Karina E et al. (2014) Canine retina has a primate fovea-like bouquet of cone photoreceptors which is affected by inherited macular degenerations. PLoS One 9:e90390
Goldstein, Orly; Jordan, Julie Ann; Aguirre, Gustavo D et al. (2013) A non-stop S-antigen gene mutation is associated with late onset hereditary retinal degeneration in dogs. Mol Vis 19:1871-84
Cideciyan, Artur V; Jacobson, Samuel G; Beltran, William A et al. (2013) Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement. Proc Natl Acad Sci U S A 110:E517-25
Kun, Teri; Lyons, Leslie A; Sacks, Benjamin N et al. (2013) Developmental validation of Mini-DogFiler for degraded canine DNA. Forensic Sci Int Genet 7:151-8
Kukekova, Anna V; Temnykh, Svetlana V; Johnson, Jennifer L et al. (2012) Genetics of behavior in the silver fox. Mamm Genome 23:164-77
Miyadera, Keiko; Acland, Gregory M; Aguirre, Gustavo D (2012) Genetic and phenotypic variations of inherited retinal diseases in dogs: the power of within- and across-breed studies. Mamm Genome 23:40-61
Genini, Sem; Beltran, William A; Aguirre, Gustavo D (2012) Development and validation of a canine-specific profiling array to examine expression of pro-apoptotic and pro-survival genes in retinal degenerative diseases. Adv Exp Med Biol 723:353-63

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