The Efficacy of combination therapy in Osteogenesis Imperfecta

联合治疗成骨不全症的疗效

基本信息

批准号：
8900679
负责人：
Matthew L Warman
金额：
$ 27.18万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8900679
关键词：
Affect Age Alendronate Alleles Anabolic Agents Anabolism Animals Antibodies Antibody Therapy Biological Availability Bone Density Bone Matrix Bone Pain Breeding Catabolism Childhood Clinical Trials Collagen Gene Collagen Type I Combined Modality Therapy Couples Data Disease Dual-Energy X-Ray Absorptiometry Epilepsy Femur Fluorochrome Foundations Fracture Fracture Healing Funding Genes Genetic Hereditary Disease Human Immune System Diseases Incidence Label Lead Malignant Neoplasms Measures Methods Missense Mutation Modeling Mus Mutation Osteogenesis Osteogenesis Imperfecta Osteopenia Outcome Pathway interactions Patients Pharmaceutical Preparations Phase III Clinical Trials Progressive Diaphyseal Dysplasia Property Publishing Randomized Regimen Research Personnel Resolution Roentgen Rays Severities Signal Pathway Signal Transduction Skeleton Syndrome TGFB1 gene Testing Therapeutic Time Transforming Growth Factor beta Wild Type Mouse bisphosphonate bone bone mass bone strength effective therapy experience improved lipoprotein receptor-related protein 6 mouse model neutralizing antibody prevent public health relevance research study response skeletal skeletal disorder spine bone structure therapy duration treatment strategy

项目摘要

DESCRIPTION (provided by applicant): We hypothesized that enhancing LRP5 signaling, which is pro-anabolic, would be an effective treatment strategy for patients with Osteogenesis Imperfecta (OI), a genetic disorder that affects nearly 28,000 US citizens. We tested our hypothesis using 4 different mouse models of OI by breeding these mice to a strain that has the high bone mass causing Lrp5A214V allele and by giving a SOST inhibitory antibody (Scl-Ab). We found that enhancing LRP5 signaling, genetically via the Lrp5A214V allele or pharmacologically via Scl-Ab, improved bone properties in each OI model. We now want to determine whether the gains in bone mass and strength from anti-SOST therapy continue to increase as the duration of therapy is lengthened, whether anti-SOST therapy is superior to anti-resorptive therapy in OI mice, and whether increases caused by Scl-Ab will be maintained by "consolidating" the anabolic response with an anti-resorptive therapy. We will compare Scl-Ab versus Alendronate, and also randomize 12-week-old OI mice that had received vehicle or Scl-Ab to next receive vehicle or Alendronate an additional 12 weeks. We will evaluate bone properties using a variety of measures including multi-fluorochrome labeling and quantitative histomorphometry, high resolution X-ray for fracture, DEXA for bone mineral density and total bone mass, µCT for microstructure, and whole femur 3-point bending and vertebral compression for bone strength. We also want to test whether a "combination" therapy that couples enhancing LRP5 signaling and inhibiting TGFß signaling is better than either therapy alone. Studies from several investigators suggest that TGFß over-activity is deleterious to bone and is a common occurrence in OI. Also, although we found that enhancing LRP5 signaling significantly improved bone properties in mice with moderate to severe OI, it did not bring their bone properties to those of their wild-type littermates that received the same therapy. Therefore, there is room for further improvement in the way we will treat moderate and severe OI. We will enhance LRP5 signaling in wild-type mice and mice with OI using the Lrp5A214V allele and then randomize the animals to receive the TGFß inhibitory antibody 1D11. We will compare bone properties in the wild-type and OI mice, with and without enhanced LRP5 signaling, and with and without TGFß inhibition. We hope these proof of principle experiments will show that the improvement in bone properties caused by pharmacologic enhancement of LRP5 signaling is better than by anti-resorptive therapy, does not plateau over time and, if needed, can be "consolidated" with an anti-resorptive therapy. We also will determine whether a "combination" therapy that targets two important signaling pathways in bone is superior to targeting either pathway alone. These experiments will create a scientific foundation that will provide guidance regarding which OI patients are most likely to benefit from new therapies and what therapeutic regimens will provide the best outcome.

描述（由申请人提供）：我们追求增强促合成代谢的 LRP5 信号传导将成为成骨不全症 (OI) 患者的有效治疗策略，这是一种影响近 28,000 名美国公民的遗传性疾病，我们使用该方法检验了我们的假设。通过将这些小鼠与具有导致 Lrp5A214V 等位基因的高骨量的品系进行繁殖并给予 SOST 抑制抗体，建立了 4 种不同的 OI 小鼠模型(Scl-Ab)。我们发现，通过 Lrp5A214V 等位基因从基因角度或通过 Scl-Ab 从药理学角度增强 LRP5 信号传导，可以改善每个 OI 模型的骨质量和强度。随着治疗时间的延长，治疗持续增加，抗 SOST 治疗是否优于 OI 小鼠的抗吸收治疗，以及 Scl-Ab 引起的增加是否会被维持通过抗再吸收疗法“巩固”合成代谢反应我们将比较 Scl-Ab 与阿仑膦酸钠，并将接受载体或 Scl-Ab 的 12 周龄 OI 小鼠随机分组，再接受载体或阿仑膦酸钠 12 周。我们将使用多种措施评估骨骼特性，包括多荧光染料标记和定量组织形态测定、高分辨率骨折 X 射线、DEXA 骨矿物质密度和总骨量。我们还想测试增强 LRP5 信号传导和抑制 TGFβ 信号传导的“组合”疗法是否比单独的任一疗法更好。研究人员认为，TGFβ 过度活动对骨骼有害，并且在 OI 中很常见。此外，虽然我们发现增强 LRP5 信号传导可显着改善中度至重度 OI 小鼠的骨骼特性，但事实并非如此。因此，我们治疗中度和重度成骨不全症的方法还有进一步改进的空间，我们将增强野生型小鼠和患有成骨不全症的小鼠的LRP5信号传导。使用 Lrp5A214V 等位基因进行 OI，然后随机分配动物接受 TGFß 抑制性抗体 1D11 我们将比较野生型和 OI 小鼠的骨特性，无论是否有增强的 LRP5 信号传导，以及是否有增强的 LRP5 信号传导。我们希望这些原理性实验证明能够表明 LRP5 信号传导的药物增强所引起的骨特性改善优于抗再吸收治疗，并且不会随着时间的推移而趋于稳定，并且如果需要，可以通过药物“巩固”。我们还将确定针对骨骼中两个重要信号通路的“组合”疗法是否优于单独针对其中任何一个通路。这些实验将为哪些 OI 患者最严重提供指导。可能从新疗法中受益以及哪些治疗方案将提供最佳结果。