MARROW STROMAL CELLS IN OSTEOGENESIS IMPERFECTA MODEL

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DESCRIPTION (provided by applicant): Osteogenesis Imperfecta (OI) that has an incidence of 1/10,000 - 1/20,000 live births, has frequently served as a model disorder for dominant negative conditions of structural proteins. Effective therapy for these disorders will require direct or targeted replacement of a mutated gene with wild-type allele. This research proposal will explore the possibility that patients with OI can potentially be treated with their own osteoprogenitors by gene-engineering the cells from their bone marrow that are referred to as mesenchymal stem cells or marrow stromal cells (MSCs). The marrow stromal cells will be used to test the hypothesis that marrow stromal cells from the patients with OI can be gene-engineered to correct the deleterious effects of mutations in type I collagen that produce the disease. The Specific Aims for this proposal are: (1) To obtain homologous recombination of the COL1A1 gene in human MSCs to determine the possibility of alleviating the OI symptoms by replacing the mutant allele with wild type allele of COL1A1 (2) To obtain over-expression clones of hMSCs that express COL1A1 cDNA to determine the effect of ratio of wild-type to mutant COL1A1 protein (3) To study the repair potential and homing of gene engineered hMSCs; the repair potential of gene engineered MSCs will be determined by injecting the cells into the fracture model and control mice.