Targeted Bone Regeneration via Activation of Resident Stem Cells

通过激活常驻干细胞进行定向骨再生

基本信息

批准号：
10253936
负责人：
Sharie Haugabook
金额：
$ 137.76万
依托单位：
NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10253936
关键词：
Acute Pain Autologous Transplantation Biodistribution Biological Response Modifier Therapy Bone Malalignment Bone Morphogenetic Proteins Bone Regeneration Bone Transplantation Cell Differentiation process Cell membrane Clinical Trials Complex Data Development Disadvantaged Dose Fracture Fracture Healing Goals Harvest Hemorrhage Hospitalization Human Implant Inflammation Injectable Injury Investigational New Drug Application Lead Medical Mesenchymal Stem Cells Methods Morbidity - disease rate Operating Rooms Operative Surgical Procedures Pain Patient Recruitments Patients Pharmaceutical Preparations Physiological Plasmids Procedures Quality of life Recombinant Proteins Risk Scientist Site Spine surgery Surgeon Technology Time Toxicology Ultrasonography United States United States Food and Drug Administration Weight-Bearing state bone bone healing bone morphogenetic protein 2 bone morphogenetic protein 6 chronic pain compliance behavior first-in-human healing in vivo long bone new technology novel therapeutics plasmid DNA pre-clinical preclinical development protein expression repaired research clinical testing scaffold side effect sonoporation stem cells tissue stem cells

项目摘要

in-human clinical trials to treat severe bone fractures. Summary of activities: More than 1 million severe bone fractures each year fail to heal, resulting in non-union. Current treatments include the use of autografts or bone transport. Limitations associated with autografts harvesting bone from elsewhere in the patients body for use at the site of injury include the need for an additional surgical procedure with the associated morbidity, increased bleeding and operating room time, acute pain during the procedure, and chronic pain post-implant. Bone transport requires an external circular, modular fixator that is fixed to the broken bone via heavy-gauge wires. The fixator allows for partial weight bearing while applying tension to the fractured bone, inducing gradual bone regeneration. Its disadvantages include pain, multiple surgeries, poor patient compliance, inconvenience of the frame, risk of inducing bone malalignment, and a complicated procedure for the surgeon. An alternative approach is the use of bone morphogenetic protein (BMP) to induce bone regeneration. An existing therapy uses BMP-2, but it is mainly used for spinal surgery rather than repair of long bones. Recombinant proteins have short half-lives, requiring large doses that can lead to inflammation and other unwanted side effects. To overcome the limitations of current treatments, the lead collaborators developed a new technology, called SonoHeal, that attracts and activates endogenous tissue stem cells to regenerate bone and heal fractures. First, a biodegradable scaffold is implanted into the fracture site, which recruits the patients own mesenchymal stem cells (MSCs). At a second step, BMP-6 plasmid is delivered to the MSCs via sonoporation the use of transcutaneous ultrasound to transfer plasmid DNA across the cell membrane resulting in BMP-6 protein expression at a physiological level to induce cell differentiation and promote the formation of new bone and fracture healing. BrIDGs scientists have initiated a preclinical development campaign to advance the SonoHeal technology to clinical evaluation. Planned activities include development of bioanalytical methods, in vivo efficacy and biodistribution studies, manufacture and characterization of the injectable drug product, and the toxicology studies needed to support an Investigational New Drug (IND) application to the Food and Drug Administration (FDA).

内人类临床试验以治疗严重的骨折。活动摘要：每年超过100万个严重的骨折无法治愈，导致非工会。当前的处理包括使用自体移植或骨运输。与自体移植相关的局限性在受伤部位从患者体内收集骨骼，包括需要进行额外的外科手术，并具有相关的发病率，出血和手术室时间增加和手术室时间，手术过程中的急性疼痛以及慢性疼痛后植入术后。骨运输需要一个外部的圆形模块化固定器，该固定器通过重孔线固定在骨折的骨头上。固定器允许在骨折骨上施加张力时进行部分负重，从而诱导逐渐的骨骼再生。它的缺点包括疼痛，多次手术，患者的依从性差，框架的不便，诱发骨骼疾病的风险以及对外科医生的复杂手术。另一种方法是使用骨形态发生蛋白（BMP）诱导骨骼再生。现有的疗法使用BMP-2，但主要用于脊柱手术，而不是修复长骨头。重组蛋白的半衰期短，需要大剂量，这会导致炎症和其他不必要的副作用。为了克服当前治疗的局限性，主要合作者开发了一种称为Sonoheal的新技术，该技术吸引和激活内源性组织干细胞以再生骨骼和治愈骨折。首先，将可生物降解的支架植入骨折部位，该部位招募了患者自己的间充质干细胞（MSC）。在第二步中，BMP-6质粒通过超声处理将经皮超声传递到MSC中，以将质粒DNA转移到细胞膜上，从而在生理水平上在生理水平上表达BMP-6蛋白表达，从而诱导细胞分化并促进新骨和骨骼疾病的形成。 Bridgs科学家发起了一项临床前开发运动，以将Sonoheal技术推向临床评估。计划的活动包括开发生物分析方法，体内功效和生物分布研究，可注射药物产品的制造和表征以及支持研究新药（IND）在食品和药物管理局（FDA）中所需的毒理学研究。