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：
10910760
负责人：
Tracey Rogers
金额：
$ 282.05万
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/10910760
关键词：
Acute Pain Antibodies Autologous Transplantation BMP6 gene Biodistribution Biological Response Modifier Therapy Bone Malalignment Bone Morphogenetic Proteins Bone Regeneration Cell Differentiation Induction Cell membrane Clinical Clinical Trials Complex Data Development Disadvantaged Dose Drug Kinetics Evaluation Fracture Goals Harvest Hemorrhage 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 Recombinant Proteins Risk Sampling Scientist Site Surgeon Technology Time Toxicology United States United States Food and Drug Administration Weight-Bearing state biodegradable scaffold bone bone fracture repair bone healing chronic pain compliance behavior efficacy study first-in-human healing in vivo manufacture new technology novel therapeutics plasmid DNA pre-clinical preclinical development protein expression research clinical testing side effect sonoporation stem cells tissue stem cells ultrasound

项目摘要

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 are continuing preclinical development efforts to advance the SonoHeal technology to clinical evaluation. The team completed an in vivo efficacy study, developed a human BMP-6 bioanalytical method, and manufactured the clinical grade injectable drug product (pCMV-BMP-6) to be used in subsequent human trials. Ongoing activities include continued development of additional bioanalytical methods and analyses of samples to support GLP toxicology studies, pharmacokinetic biodistribution studies, and evaluation of anti-drug antibodies. Completion of these activities will enable the collaborators to file an Investigational New Drug (IND) application to the Food and Drug Administration (FDA).

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科学家正在继续进行临床前开发工作，以将Sonoheal技术推向临床评估。该小组完成了一项体内功效研究，开发了人类BMP-6生物分析方法，并制造了可在随后的人类试验中使用的临床级可注射药物（PCMV-BMP-6）。正在进行的活动包括持续开发其他生物分析方法以及对支持GLP毒理学研究，药代动力学生物分布研究的样品分析以及抗药物抗体的评估。这些活动的完成将使合作者能够向食品和药物管理局（FDA）提出研究新药（IND）。