Development and Characterization of a Preclinical Swine Model of Osteogenesis Imperfecta

PROJECT SUMMARY Osteogenesis imperfectaOIalso known asbrittle bone diseaseis a genetic disease in which patients have defects in the formationstructureor strength of their bonescausing them to break easilyOI patients exhibit impaired tissue development and bone regeneration due to inherited mutations in one of the collagen genesleading to skeletal defectsbone fragilitydentinogenesis imperfectahearing lossand premature deathThe clinical manifestations of OI vary from a mild increase in fractures to severe bone deformities and death in the neonatal periodTo datethere 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 prioritizationpatient recruitmentand integrating new therapies into OI clinical careAdditionallythere are major hurdles in the development of safe and effective treatments for OIfirstthe mouse models do not fully recapitulate the disease seen in patients and have been poor predictors of clinical efficacySeconddue to a small patient population and orphan disease statusthe ability to recruit enough patients for clinical trials is nearly impossibleOur 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 trialsHerewe 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 OIand 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 osteoporosisIn addition to serving as a large animal preclinical model for therapeutic safety and efficacythis model will provide an ideal platform toimprove our understanding of DGI and craniofacial abnormalitiesdevelop techniques for in vivo gene editing and gene therapydevelop orthopedic devices for intramedullary roddingdevelop noninvasive techniques for malocclusionandunderstand the natural progression of bone mineralization after currently available therapeutics PROJECT NARRATIVE Osteogenesis imperfectaOIalso known asbrittle bone diseaseis a genetic disease in which patients have defects in the formationstructureor strength of their bonescausing them to break easilyTo datethere 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 prioritizationpatient recruitmentand integrating new therapies into OI clinical careHerewe 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 OIand 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