Sclerostin Antibody Therapy for Treatment of Osteogenesis Imperfecta

描述（由申请人提供）：成骨不全症（Osteogenesis imperfecta， OI）是一种I型胶原或胶原相关蛋白的遗传性疾病，导致严重的骨脆性。虽然对导致成骨不全的基因突变了解很多，但治疗策略主要局限于最初为骨质疏松症开发的抗再吸收干预措施。目前对于成骨不全患者没有有效的合成代谢治疗选择。最近发现的蛋白质硬化蛋白作为成骨细胞活性的负调节因子导致了合成代谢硬化蛋白抗体的发展。硬化蛋白抗体（SclAb）治疗要想有效治疗成骨不全症，必须激活含有胶原蛋白缺陷的成骨细胞，增加骨量，降低骨脆性。本提案的目的是了解在成骨不全小鼠模型中，与双膦酸盐（BP）治疗相比，SclAb治疗对骨细胞活性、质量和材料质量的不同影响。Brtl/+小鼠再现了成骨不全患者的细胞、生物力学和衰老表型，并已被有效地用于评估成骨不全患者的BP治疗。在本提案中，BP和SclAb抗体在控制组织质量和材料特性中的作用将被评估。将评估临床前治疗和联合治疗。该建议的中心假设是，SclAb治疗将降低骨脆性，因此骨脆弱性将需要保护性BP治疗，以防止骨量的短暂增加随着时间的推移而减少，但不会因先前或与BP联合治疗而减弱。然而，与BP联合治疗前或联合治疗可能会导致SclAb治疗中持续存在的变化，潜在地将骨骼置于单独使用BP治疗时观察到的并发症的风险中。利用荧光引导的生物力学模型，设计在多个层次上测试骨脆性，这些治疗方案的影响将根据药物时间和组织年龄进行量化。本研究结果将直接影响未来成骨不全患者的临床治疗策略。此外，这些研究将产生关键数据，确定控制成骨细胞和破骨细胞活性的调节因子如何影响成骨不全骨骼中多个尺寸尺度的组织质量参数，并对骨质疏松症等其他疾病具有重要意义，其中BP是常见的，并提出了SclAb治疗。

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.