Sclerostin Antibody Therapy for Treatment of Osteogenesis Imperfecta

描述（由申请人提供）：成骨不全（OI）是一种I型胶原或胶原相关蛋白导致严重骨脆性的遗传性疾病。虽然关于导致骨质疏松症的基因突变已经知道很多，但治疗策略主要限于最初为骨质疏松症开发的抗吸收干预。目前对于OI患者没有有效的合成代谢治疗选择。最近发现的蛋白质sclerostin作为成骨细胞活性的负调节剂，导致了合成代谢sclerostin抗体的发展。对于硬化蛋白抗体（SclAb）疗法有效治疗OI，它必须激活携带胶原缺陷的成骨细胞，增加骨量，并降低疾病的骨脆性特征。 本提案的目的是了解在OI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。Brt 1/+小鼠再现了OI患者的细胞、生物力学和衰老表型，并已有效地用于评估针对OI的BP疗法。在本提案中，将评价BP和SclAb抗体在控制组织质量和材料特性方面的作用。将评价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，因此骨脆性将需要保护性BP治疗以防止骨量的暂时性增加随时间减少，但不会被先前或与BP的联合治疗所减弱。然而，BP的预治疗或联合治疗可能会引起SclAb治疗持续存在的变化，可能使骨骼处于单独使用BP治疗时观察到的并发症的风险中。 使用荧光引导的生物力学模型，旨在测试多个层次的骨脆性，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。这项研究的结果将直接影响OI患者未来的临床治疗策略。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OI骨骼中多个尺寸尺度的组织质量参数，并且对于其他疾病（如骨质疏松症）非常重要，BP使用是常见的，并且提出了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.