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：
10685887
负责人：
Sharie Haugabook
金额：
$ 302.55万
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/10685887
关键词：
Acute Pain Antibodies Autologous Transplantation BMP2 gene BMP6 gene 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 Drug Kinetics Evaluation Fracture Goals Harvest Hemorrhage Hospitalization 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 Sampling Scientist Site Spine surgery Surgeon Technology Time Toxicology United States United States Food and Drug Administration Weight-Bearing state biodegradable scaffold bone bone fracture repair chronic pain compliance behavior efficacy study first-in-human healing in vivo long bone new technology novel therapeutics plasmid DNA pre-clinical preclinical development protein expression repaired research clinical testing side effect sonoporation stem cells tissue stem cells ultrasound

项目摘要

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. TDB scientists have begun preclinical development efforts to advance the SonoHeal technology to clinical evaluation. Ongoing activities include continued development of bioanalytical methods, an in vivo efficacy study, bioanalytical sample analyses to support GLP toxicology studies, pharmacokinetic biodistribution studies, and evaluation of anti-drug antibodies. Completed studies include GMP manufacture of the injectable drug product, pCMV-BMP-6. Completion of all these activities will enable the collaborators to file an Investigational New Drug (IND) application to the Food and Drug Administration (FDA).

每年有超过100万个严重的骨骼骨折无法愈合，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。 TDB科学家已经开始临床前开发工作，以将Sonoheal技术推向临床评估。正在进行的活动包括持续开发生物分析方法，一项体内疗效研究，生物分析样品分析以支持GLP毒理学研究，药代动力学生物分布研究以及抗药物抗体的评估。完成的研究包括GMP生产可注射药物PCMV-BMP-6。所有这些活动的完成将使合作者能够向食品药品监督管理局（FDA）提出研究新药（IND）。