This proposal describes a five-year training program to develop an academic career in Medical Genetics and gene therapy. The program will further advance the investigator's research in the development of an AAV-mediated gene targeting strategy for the treatment of Osteogenesis Imperfecta. The investigator will be mentored by Dr. David Russell, well recognized for his achievements in developing the adeno-associated virus (AAV) vector system for gene targeting. Osteogenesis Imperfecta (01) is a group of inherited collagen disorders characterized by bone fragility with clinical manifestations varying from a mild increase in fractures to severe bone deformities and death. Mutations that cause Ol are located in the COL1A1 and COL1A2 genes. Current treatment options are limited and do not alleviate the complications seen in Ol. Most gene therapy systems involve the process of gene addition, where a promoter and a gene are delivered into a cell and integrate randomly. In contrast, gene targeting uses homologous sequences to alter the cell's endogenous genes in a site specific manner. By this method mutated genes can be either "knocked-out" or corrected. The major advantage of gene targeting is that genes can be modified at their proper location on the chromosme without disrupting cellular gene regulation. Previous work by Dr. Russell has demonstrated that an AAV-mediated gene targeting vector can target the COL1A1 gene and disrupt dominant negative mutant procollagen production. It was shown that the loss of the mutant protein improved the processing, stability and structure of the collagen fibril. The objective of this proposal is to develop an AAV gene targeting vector that will target the COL1A2 gene, reduce random integration, and target multiple individuals with Ol.
The specific aims i nclude: 1) Develop an AAV gene-targeting vector to target the COL1A2 gene in Ol;2) Develop an improved AAV gene-targeting vector to reduce the recovery of random integrants;and 3) Determine the effects of human variation on gene targeting. The completion of this project and the training received at the University of Washington will prepare the principle investigator to be a leading researcher in gene therapy.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Clinical Investigator Award (CIA) (K08)
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Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
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Chen, Faye H
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Mayo Clinic, Rochester
United States
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Deyle, David R; Hansen, R Scott; Cornea, Anda M et al. (2014) A genome-wide map of adeno-associated virus-mediated human gene targeting. Nat Struct Mol Biol 21:969-75
Deyle, David R; Li, Li B; Ren, Gaoying et al. (2014) The effects of polymorphisms on human gene targeting. Nucleic Acids Res 42:3119-24
Deyle, David R; Khan, Iram F; Ren, Gaoying et al. (2012) Normal collagen and bone production by gene-targeted human osteogenesis imperfecta iPSCs. Mol Ther 20:204-13
Deyle, David R; Russell, David W (2009) Adeno-associated virus vector integration. Curr Opin Mol Ther 11:442-7