Sclerostin Antibody Therapy for Treatment of Osteogenesis Imperfecta

硬化蛋白抗体疗法治疗成骨不全症

• 批准号: 9081526
• 负责人: Kenneth M Kozloff
• 金额: $ 33.69万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-24 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9081526
• 关键词: Adult; Aftercare; Age; Aging; Animals; Antibodies; Antibody Therapy; Basic Science; Biomechanics; Bone Diseases; COL1A1 gene; Calcified; Cartilage; Cells; Characteristics; Childhood; Clinical; Clinical Treatment; Collagen; Collagen Type I; Combined Modality Therapy; DNA Sequence Alteration; Data; Defect; Development; Disease; Fluorescence; Fracture; Future; Gene Targeting; Goals; Growth; Growth and Development function; Hereditary Disease; Intervention; Knock-in; Laboratories; Mechanics; Modeling; Monitor; Mus; Mutation; Osteoblasts; Osteoclasts; Osteogenesis; Osteogenesis Imperfecta; Osteoporosis; Patients; Pharmaceutical Preparations; Phenotype; Population; Predisposition; Production; Property; Proteins; Quality of life; Recovery; Research; Risk; Role; Signal Transduction; Skeleton; Study models; Techniques; Testing; Time; Tissues; Up-Regulation; Wild Type Mouse; base; biomechanical model; bisphosphonate; bone; bone age; bone cell; bone mass; bone strength; cathepsin K; effective therapy; fluorescence imaging; functional outcomes; image guided; improved; in vivo; indexing; model design; mouse model; novel; novel strategies; pre-clinical; prevent; therapy outcome; treatment strategy

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.

描述（由申请人提供）：成骨不全症（OI）是一种 I 型胶原蛋白或胶原蛋白相关蛋白的遗传性疾病，导致严重的骨骼脆性。虽然人们对导致成骨不全的基因突变了解很多，但治疗策略主要限于最初针对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。最近发现硬化蛋白作为成骨细胞活性的负调节剂，导致了合成代谢硬化蛋白抗体的开发。为了使硬化素抗体 (SclAb) 疗法能够有效治疗成骨不全症，它必须激活具有胶原缺陷的成骨细胞，增加骨量，并降低该疾病特征的骨脆性。 该提案的目的是了解在 OI 小鼠模型中，与双磷酸盐 (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 OI 患者的细胞、生物力学和衰老表型，并已有效地用于评估 OI 的 BP 疗法。在该提案中，将评估 BP 和 SclAb 抗体在控制组织质量和材料特性中的作用。将评估临床前治疗和联合疗法。该提案的中心假设是，SclAb 治疗将降低骨脆性，因此骨脆性将需要保护性 BP 治疗，以防止短暂的骨量增加随着时间的推移而减少，但不会因先前或联合 BP 治疗而减弱。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，可能使骨骼面临单独 BP 治疗时观察到的并发症的风险。 使用旨在在多个层次上测试骨脆性的荧光引导生物力学模型，将根据药物时机和组织年龄来量化这些治疗方案的影响。这项研究的结果将直接影响成骨不全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素如何影响 OI 骨骼中多个尺寸尺度的组织质量参数，并且对于骨质疏松症等其他疾病很重要，BP 的使用很常见，并且提出了 SclAb 治疗。

项目成果

Rapidly growing Brtl/+ mouse model of osteogenesis imperfecta improves bone mass and strength with sclerostin antibody treatment.

• DOI: 10.1016/j.bone.2014.10.012
• 发表时间: 2015-02
• 期刊: BONE
• 影响因子: 4.1
• 作者: Sinder, Benjamin P.;Salemi, Joseph D.;Ominsky, Michael S.;Caird, Michelle S.;Marini, Joan C.;Kozloff, Kenneth M.
• 通讯作者: Kozloff, Kenneth M.

Sclerostin antibody improves skeletal parameters in a Brtl/+ mouse model of osteogenesis imperfecta.

• DOI: 10.1002/jbmr.1717
• 发表时间: 2013-01
• 期刊: JOURNAL OF BONE AND MINERAL RESEARCH
• 影响因子: 6.2
• 作者: Sinder, Benjamin P.;Eddy, Mary M.;Ominsky, Michael S.;Caird, Michelle S.;Marini, Joan C.;Kozloff, Kenneth M.
• 通讯作者: Kozloff, Kenneth M.

Low Dose of Bisphosphonate Enhances Sclerostin Antibody-Induced Trabecular Bone Mass Gains in Brtl/+ Osteogenesis Imperfecta Mouse Model.

• DOI: 10.1002/jbmr.3421
• 发表时间: 2018-07
• 期刊: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
• 作者: Olvera D;Stolzenfeld R;Marini JC;Caird MS;Kozloff KM
• 通讯作者: Kozloff KM

Adult Brtl/+ mouse model of osteogenesis imperfecta demonstrates anabolic response to sclerostin antibody treatment with increased bone mass and strength.

成年 Brtl/+ 成骨不全小鼠模型表现出对硬化素抗体治疗的合成代谢反应，骨量和强度增加。

• DOI: 10.1007/s00198-014-2737-y
• 发表时间: 2014-08
• 期刊: OSTEOPOROSIS INTERNATIONAL
• 影响因子: 4
• 作者: Sinder, B. P.;White, L. E.;Salemi, J. D.;Ominsky, M. S.;Caird, M. S.;Marini, J. C.;Kozloff, K. M.
• 通讯作者: Kozloff, K. M.