Targeting Therapeutics for Accelerated Bone Fracture Repair

项目摘要/摘要 意义：老年患者骨折未能得到充分修复会导致显著的发病率。 以及美国每年的死亡率。老龄化将继续加剧这一问题 预计到2040年，仅髋部骨折就会增加160%，失去工作的成本也很高， 生活质量、物理治疗、长期护理设施住宿和手术。传统疗法包括 机械稳定骨折，但到目前为止，还没有系统的骨合成代谢疗法存在的靶向和 加快骨折修复。 初步数据：Novosteo Inc.已经开发出一种骨折靶向疗法，该疗法已经证明 愈合时间和骨痂形成显著加快，对骨折部位有显著的特异性。 通过皮下注射全身给药，药物选择性地积聚在羟基磷灰石上， 骨折中露出的无机物部分，提供特定部位剂量的合成代谢剂。目标人群 骨折痂的特异性限制了药物在非靶向组织中的累积，降低了副作用的可能性 效果。此外，全身给药途径允许给予多剂量的合成代谢剂。 而不是通过手术一次给药。在绕过手术的侵入性的同时，这种药物模仿了一种局部- 给予合成代谢药物，因为药物积聚仅限于骨折部位，足够的剂量可以 用来加速愈合的。到目前为止，Novosteo的生物分布研究表明没有 可检测到的毒性极大地加速了骨折的修复。 建议：此快速通道SBIR建议的总体目标将是准备建议的骨折靶向 临床试验的治疗方法。第一步将是优化Novosteo领先候选人的化学成分。这将是 通过执行以下步骤在第一阶段完成：(1)骨折靶向配体的优化 (2)对骨折靶向药物的毒性进行彻底的分析。第二阶段将重点放在 为IND准备骨折靶向药物。这将通过以下方式完成：(1)验证阶段I结果为 非啮齿动物模型，(2)进行MTD、GLP药代动力学和GLP毒性研究，以及(3)进行 进行遗传毒性分析，以评估任何形态遗传危险。 结论：加速骨折修复的能力是尚未解决的基本需求 用传统的方法。如果获得批准，拟议研究的完成将使优化和 骨折修复不可缺少的治疗方法的临床前评估。它的安全性和有效性可以是 在其他需要加速骨再生的环境中进行探索和评估，例如发际线 骨质疏松患者的椎体骨折或颅面重建和修复。

Project Summary/Abstract Significance: The failure of bone fractures to adequately repair in elderly patients causes significant morbidity and mortality each year in the United States. This problem will continue to be exacerbated by an aging population, with a 160% increase in hip fractures alone expected by 2040 and significant costs in lost work, quality of life, physical therapy, extended care facility stays, and surgeries. Conventional therapy includes mechanically stabilizing the fracture, but thus far, no systemic bone anabolic therapies exist to target and accelerate fracture repair. Preliminary Data: Novosteo Inc. has developed a fracture targeted therapeutic that has demonstrated a dramatic acceleration in healing time and callus formation and remarkable specificity to bone fracture sites. Administered systemically through subcutaneous injection, the drug selectively accumulates on hydroxyapatite, the inorganic portion of bone exposed in a fracture, providing a site-specific dose of anabolic agent. The targeted specificity to the fracture callus limits accumulation of the drug in off-target tissues, reducing the potential for side effects. Also, the systemic delivery route allows for multiple doses of anabolic agent to be administered rather than a single bolus possible via surgery. While bypassing the invasiveness of surgery, the drug mimics a locally- administered anabolic in that drug accumulation is limited to the fracture site and sufficient dose can be administered for accelerated healing. Thus far, Novosteo's biodistribution studies have demonstrated no detectable toxicities at doses that dramatically accelerate fracture repair. Proposal: The overall goal of this Fast-Track SBIR proposal will be to prepare the proposed fracture-targeted therapy for clinical trials. The first step will be to optimize the chemistry of Novosteo's lead candidate. This will be accomplished in Phase I by performing the following: (1) optimization of the fracture targeting ligand composition and (2) conducting a thorough analysis of the fracture targeted drug's toxicity. Phase II will focus on preparing the fracture targeted drug for IND. This will be accomplished by: (1) validating Phase I results in a non-rodent model, (2) conducting MTD, GLP pharmacokinetics, and GLP toxicity studies, and (3) conducting genotoxicity analysis to evaluate any morphogenic dangers. Conclusion: The ability to accelerate bone fracture repair is a fundamental need that has not been addressed by conventional methods. If granted, the completion of the proposed studies would enable the optimization and pre-clinical evaluation of an indispensable therapy for bone fracture repair. Its safety and efficacy could then be explored and evaluated in other settings where accelerated bone regeneration is desired, such as hairline vertebral fractures in osteoporosis patients or craniofacial reconstruction and repair.