PROJECT SUMMARY Osteogenesis imperfecta (OI), also known as ?brittle bone disease?, is a genetic disease in which patients have defects in the formation, structure, or strength of their bones, causing them to break easily. OI patients exhibit impaired tissue development and bone regeneration due to inherited mutations in one of the collagen genes, leading to skeletal defects, bone fragility, dentinogenesis imperfecta, hearing loss, and premature death. The clinical manifestations of OI vary from a mild increase in fractures to severe bone deformities and death in the neonatal period. To date, there is no treatment that corrects the underlying cause or alleviates the complications seen in OI and the development of therapeutics for OI has challenges including candidate drug prioritization, patient recruitment, and integrating new therapies into OI clinical care. Additionally, there are major hurdles in the development of safe and effective treatments for OI: first, the mouse models do not fully recapitulate the disease seen in patients and have been poor predictors of clinical efficacy. Second, due to a small patient population and orphan disease status, the ability to recruit enough patients for clinical trials is nearly impossible. Our goal is to establish a swine model of OI that recapitulates the disease seen in OI patients to better understand disease etiology and progression and provide a reliable preclinical model for establishing safety and efficacy of new therapies prior to clinical trials. Here, we aim to develop a large animal model of OI that will serve as a platform for identifying and testing novel therapeutics and drug combinations for OI, and provide valuable insight into the biological mechanisms that govern tissue regeneration and can lead to new therapeutic discoveries for more common high bone turnover human diseases like osteoporosis. In addition to serving as a large animal preclinical model for therapeutic safety and efficacy, this model will provide an ideal platform to 1) improve our understanding of DGI and craniofacial abnormalities, 2) develop techniques for in vivo gene-editing and gene therapy, 3) develop orthopedic devices for intramedullary rodding, 4) develop noninvasive techniques for malocclusion, and 5) understand the natural progression of bone mineralization after currently available therapeutics.
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