Sclerostin Antibody Therapy for Treatment of Osteogenesis Imperfecta

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION (provided by applicant): Osteogenesis imperfecta (OI) is a genetic disease of type I collagen or collagen-related proteins leading to severe bone fragility. While much is known regarding the genetic mutations leading to OI, treatment strategies have been limited primarily to anti-resorptive interventions originally developed for osteoporosis. There is currentl no effective anabolic treatment option for OI patients. The recent discovery of the protein sclerostin as a negative regulator of osteoblast activity has led to the development of anabolic sclerostin antibodies. For sclerostin antibody (SclAb) therapy to be effective in treating OI, it must activate osteoblasts harboring a collagen defect, increase bone mass, and reduce bone fragility characteristic of the disease. The objectives of this proposal are to understand the differential effects of SclAb therapy on bone cell activity, mass, and material quality when compared to bisphosphonate (BP) treatment in a mouse model of OI. The Brtl/+ mouse reproduces the cellular, biomechanical, and aging phenotype of the OI patient, and has been effectively used to evaluate BP therapies for OI. In this proposal, the role of BP and SclAb antibody in governing tissue mass and material properties will be evaluated. Pre-clinical treatment and combination therapies will be evaluated. The central hypothesis of this proposal is that SclAb therapy will decreases bone brittleness, and thus bone fragility, will require protective BP therapy to prevent transitory gains in bone mass from diminishing over time, but will not be blunted by prior or co-therapy with BP. However, pre- or co-therapy with BP may induce changes that persist with SclAb therapy, potentially placing the skeleton at risk for complications observed when treating with BP alone. Using fluorescence-guided biomechanical models designed to test bone brittleness at multiple hierarchical levels, the impact of these treatment options will be quantified based on drug timing and tissue age. Results from this study will directly impact future clinical treatment strategies for OI patients. Furthermore, these studis will yield critical data identifying how regulatory factors that govern osteoblast and osteoclast activity can influence tissue quality parameters at multiple size scales in the OI skeleton and wil be important for other diseases such as osteoporosis, for which BP use is commonplace, and SclAb therapy is proposed.