The Efficacy of combination therapy in Osteogenesis Imperfecta

联合治疗成骨不全症的疗效

• 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
• 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

 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）：我们假设增强LRP 5信号传导（其是促合成代谢的）将是成骨不全（OI）患者的有效治疗策略，OI是一种影响近28，000名美国公民的遗传性疾病。我们使用4种不同的OI小鼠模型来测试我们的假设，通过将这些小鼠繁殖到具有高骨量导致Lrp5A214V等位基因的品系，并通过给予SOST抑制性抗体（Scl-Ab）。我们发现，通过Lrp5A214V等位基因或Scl-Ab介导的LRP 5信号传导增强，可改善每种OI模型的骨特性。我们现在想确定抗SOST治疗的骨量和强度的增加是否随着治疗持续时间的延长而继续增加，抗SOST治疗是否上级优于OI小鼠的抗吸收治疗，以及Scl-Ab引起的增加是否会通过用抗吸收治疗"巩固"合成代谢反应来维持。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小鼠随机分配至下一次接受载体或阿仑膦酸钠额外12周。我们将使用多种测量方法评价骨特性，包括多荧光染料标记和定量组织形态测定、骨折的高分辨率X线检查、骨矿物质密度和总骨量的DEXA、微观结构的µ CT以及骨强度的全股骨3点弯曲和椎体压缩。我们还想测试一种结合增强LRP 5信号传导和抑制TGF β 1信号传导的"组合"疗法是否优于单独的疗法。几位研究者的研究表明，TGF β过度活性对骨有害，并且在OI中常见。此外，尽管我们发现增强LRP 5信号传导显著改善了中度至重度OI小鼠的骨特性，但它并没有将其骨特性带到接受相同治疗的野生型同窝出生小鼠的骨特性。因此，我们治疗中度和重度OI的方式还有进一步改进的空间。我们将使用Lrp5A214V等位基因增强野生型小鼠和患有OI的小鼠中的LRP5信号传导，然后将动物随机化以接受TGF β抑制性抗体1D11。我们将比较野生型和OI小鼠的骨特性，有和没有增强的LRP 5信号传导，有和没有TGF β抑制。我们希望这些原理验证实验能够表明，LRP 5信号传导的药理学增强引起的骨特性改善优于抗吸收治疗，不会随着时间的推移而趋于稳定，并且如果需要，可以通过抗吸收治疗来“巩固”。吸收疗法。我们还将确定靶向骨中两个重要信号通路的"联合"治疗是否优于单独靶向其中一个通路。这些实验将建立一个科学基础，为哪些OI患者最有可能从新疗法中受益以及哪些治疗方案将提供最佳结果提供指导。