Therapeutic Application of Painless Nerve Growth Factor to Accelerate Endochondral Fracture Repair

无痛神经生长因子加速软骨内骨折修复的治疗应用

• 批准号: 10211755
• 负责人: Chelsea Shields Bahney
• 金额: $ 48.26万
• 依托单位: STEADMAN PHILIPPON RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10211755
• 关键词: Acute; Address; Adopted; Affect; Affinity; Age; Alzheimer' s Disease; Applications Grants; Binding; Biocompatible Materials; Biological; Blood Vessels; Bone Injury; Bone Morphogenetic Proteins; Bone Regeneration; Bone Transplantation; Bone callus; Cartilage; Cells; Chondrocytes; Clinic; Clinical; Data; Development; Diabetes Mellitus; Disease; Dose; Engineering; Exhibits; FDA approved; Fracture; Fracture Healing; Goals; Grant; Heparin; Impaired healing; In Vitro; Injectable; Injury; Invaded; Kinetics; Label; Literature; Mediating; Molecular; Mus; NGFR Protein; Natural regeneration; Nerve Growth Factors; Nerve Regeneration; Neuropathy; Neurotrophic Tyrosine Kinase Receptor Type 1; Nociception; Obesity; Operative Surgical Procedures; Osteoblasts; Pain; Painless; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacotherapy; Phase; Physiologic Ossification; Population; Positioning Attribute; Pre-Clinical Model; Process; Protein Isoforms; Research; Risk; Role; Signal Pathway; Signal Transduction; Site; Smoking; Stress Fractures; Testing; Therapeutic; Time; Translating; Translations; United States; Vascularization; Work; base; beta catenin; bone; bone fracture repair; bone healing; cartilaginous; clinical efficacy; clinical translation; clinically relevant; comorbidity; cost; design; diabetic; fracture risk; healing; implantation; improved; in vivo; intramembranous bone formation; local drug delivery; long bone; mouse model; mutant; nanowire; nerve supply; neurovascular; novel; osteogenic; polycaprolactone; programs; receptor; reinnervation; repaired; response; scaffold; standard of care; tibia; transcriptome sequencing

ABSTRACT The long-term goal of this project is to develop and validate an injectable, biodegradable nanowire delivery platform for local and sustained release of a “painless” nerve growth factor (NGF) isoform to accelerate fracture healing in clinical scenarios of delayed healing. Approximately 15 million fracture injuries occur each year in the United States (US).6 An estimated 10-15% of fractures within a healthy population result in delayed- or non-union.7,8 However, delayed healing rates increase to almost 50% in patients with vascular damage or high co-morbidity burdens such as diabetes, increased age, smoking, and obesity.9,10 The current standard of care for delayed healing or non-union is surgical intervention to increase stability or to promote healing through application of bone grafts. Bone morphogenetic protein (BMP) is the only biologic with FDA approval for use in fracture repair, with “on-label” use only within a narrow indication window. However, BMP requires surgical implantation and is typically limited to only the most at-risk fractures due to the high cost, limited evidence of clinical efficacy, and risk of severe off-target effects.11-14 As such, there exists an unmet clinical need for biologics that could stimulate bone regeneration in a non-surgical delivery platform. This application builds on strong preliminary data demonstrating that NGF accelerates fracture repair when injected into the cartilaginous phase of long bone healing. Importantly, our preliminary data is the first to show that NGF acts on chondrocytes to promote programs associated with endochondral ossification (EO). The goal of this grant is to build upon these preliminary data to develop NGF into a platform suitable for clinical translation. In the first Aim, we optimize the dose and timing of a mutant form of NGF (NGFR100W) to stimulate endochondral fracture repair. NGFR100W is a novel “painless” NGF that efficiently binds to the TrkA receptor to provide the same trophic effect as wild type NGF, but fails to bind to the p75NTR receptor to significantly reduce risk of nociception.15,16 In the second Aim, we probe the mechanism by which NGF/NGFR100W stimulates fracture repair by conditionally deleting the TrkA receptor. To date the molecular pathways stimulated by therapeutic delivery of NGF have not been rigorously studied in long bone fracture healing. Lastly, in the third Aim, we modify our previously developed injectable heparin coated polycaprolactone (PCL) nanowires17 for encapsulation and sustained delivery of painless NGF. Here we also incorporate a pre-clinical model of diabetes (Lepob) established to demonstrate delayed healing to challenge our therapy in a clinically relevant scenario of malunion. These aims allow us to test the central hypothesis that a painless NGF therapy can improve fracture healing by acting through TrkA signaling to stimulate chondrocyte-to-osteoblast transformation. Our interdisciplinary team of experts in fracture healing, biomaterials, and NGF/TrkA signaling uniquely positions us to successfully accomplish the proposed study. Importantly, our approach is grounded in creating a translationally relevant therapeutic platform that has the potential to significantly improve patient outcomes following a fracture.

抽象的 该项目的长期目标是开发和验证可注射、可生物降解的纳米线输送 用于局部和持续释放“无痛”神经生长因子（NGF）异构体以加速释放的平台 骨折愈合延迟愈合的临床情况中大约发生了 1500 万例骨折损伤。 美国 (US) 每年都会发生这种情况。6 据估计，健康人群中 10-15% 的骨折会导致 延迟愈合或不愈合。7,8 然而，血管性血管病患者的延迟愈合率增加到近 50% 损害或高并发症负担，如糖尿病、年龄增长、吸烟和肥胖。9,10 延迟愈合或不愈合的护理标准是手术干预以增加稳定性或促进 骨形态发生蛋白 (BMP) 是唯一获得 FDA 批准的生物制剂。 批准用于骨折修复，仅在狭窄的适应症范围内“标签上”使用。 需要手术植入，并且由于成本高、有限，通常仅限于最危险的骨折。 临床疗效的证据，以及严重脱靶效应的风险。11-14 因此，存在未满足的临床需求 需要能够在非手术输送平台中刺激骨再生的生物制剂。 该应用建立在强有力的初步数据之上，证明 NGF 注射后可加速骨折修复 重要的是，我们的初步数据首次表明 NGF 的存在。 作用于软骨细胞以促进与软骨内骨化 (EO) 相关的程序。 赠款的目的是在这些初步数据的基础上将 NGF 开发成适合临床转化的平台。 第一个目标是，我们优化 NGF 突变体 (NGFR100W) 的剂量和时间，以刺激软骨内 NGFR100W 是一种新型“无痛”NGF，可有效结合 TrkA 受体以提供相同的效果。 具有与野生型 NGF 相同的营养作用，但无法与 p75NTR 受体结合，从而显着降低风险 nociception.15,16 在第二个目标中，我们探讨了 NGF/NGFR100W 刺激骨折修复的机制 通过有条件地删除 TrkA 受体迄今为止，治疗递送刺激的分子途径。 NGF 在长骨骨折愈合中的作用尚未经过严格研究。最后，在第三个目标中，我们修改了我们的研究。 先前开发的可注射肝素涂层聚己内酯（PCL）纳米线17用于封装和 在此，我们还纳入了建立的糖尿病临床前模型（Lepob）。 证明延迟愈合以挑战我们在临床相关的畸形愈合情况下的治疗。 让我们检验一个中心假设，即无痛 NGF 疗法可以通过作用来改善骨折愈合 我们的跨学科团队通过 TrkA 信号传导刺激软骨细胞向成骨细胞转化。 骨折愈合、生物材料和 NGF/TrkA 信号传导方面的专家使我们能够取得成功 重要的是，我们的方法基于创建翻译相关的研究。 该平台有可能显着改善骨折后患者的治疗结果。