Repair of Bone Defects with Human Autologous Pluripotent Very Small Embryonic lik

人自体多能极小胚胎样修复骨缺损

• 批准号: 8394099
• 负责人: Laurie K. McCauley
• 金额: $ 41.18万
• 依托单位: CALADRIUS BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-11 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394099
• 关键词: Absorbable Gelatin Sponge; Adult; Affect; Aftercare; American; Animals; Antibodies; Apoptosis; Area; Asses; Autologous; Bicuspid; Biopsy; Blood; Blood Component Removal; Bone Diseases; Bone Growth; Bone Injury; Bone Marrow; Bone Marrow Aspiration; Bone Regeneration; Bone Resorption; Bone Tissue; Bone necrosis; Bone remodeling; CXCR4 gene; Calcium; Calvaria; Cardiovascular Diseases; Cell Therapy; Cells; Clinical; Clinical Research; Clinical Trials; Collaborations; Color; Cyclophosphamide; Defect; Dental Implants; Dental caries; Development; Diabetes Mellitus; Disease; Double-Blind Method; Effectiveness; Embryo; Enrollment; Ethics; Evaluation; Excision; Fluorescence; Fracture; Future; Germ; Goals; Grant; Healed; Health; Heart; Human; Immunohistochemistry; Implantation procedure; In Vitro; Individual; Injury; Jaw; Label; Left; Long-Term Effects; Low Birth Weight Infant; Mandible; Marrow; Maxilla; Measures; Medical; Michigan; Modeling; Myocardial Infarction; Natural regeneration; Oral; Oral cavity; Osteoblasts; Osteogenesis; PTPRC gene; Patients; Periodontal Diseases; Periodontitis; Phase; Placebos; Pluripotent Stem Cells; Population; Procedures; Process; Property; Randomized; Reconstructive Surgical Procedures; Risk; SCID Mice; Safety; Schedule; Serum; Serum Markers; Site; Skeleton; Small Business Innovation Research Grant; Stem cells; Structure; Techniques; Testing; Tetracyclines; Therapeutic; Time; Tissues; Tooth Extraction; Tooth Socket; Tooth structure; Transplantation; Universities; X-Ray Computed Tomography; base; bone; bone healing; bone loss; cost; craniofacial; effective therapy; effectiveness measure; efficacy testing; graft vs host disease; healing; improved; in vivo; injured; osteogenic; pluripotency; reconstruction; regenerative; repaired; response to injury; skeletal; stage-specific embryonic antigen 4; standard of care; stem cell therapy; success; tissue regeneration; tissue repair; treatment site; tumor

DESCRIPTION (provided by applicant): Bone loss due to fractures and disease is a serious medical condition in the US affecting millions of Americans. It is particularly a problem with oral craniofacial disorders were the costs of treating damage exceeds $60 billion annually. Furthermore, periodontitis is associated with systemic disorders such as diabetes mellitus, preterm low birth weight, and cardiovascular disease. While major efforts have been made to understand mechanisms of healing of large bones and to develop therapeutics to treat overall bone loss, very little information is available on bone remodeling in the human craniofacial skeleton, nor the mechanisms involved in osteonecrosis of the jaw and there are few effective treatments. The results of our phase 1 SBIR showed that a unique population of human, adult, pluripotent, Very Small Embryonic like (VSEL) stem cells, have important bone regenerative properties and could be useful in treating oral-craniofacial disorders. Human VSELs are pluripotent stem cells involved in the normal turnover and regeneration of tissues and their circulating levels greatly increase in response to injury. They are able to repair injured tissues such as the heart after myocardial infarct. Adult human VSELs, are SSEA-4+/Oct-4+/CD133+/CXCR4+/Lin-/CD45-, express pluripotency markers (Oct-4 and Nanog) and are capable of differentiation into cells from all three germ lineages. With our collaborator, Dr. Russell Taichman of the University of Michigan we showed that VSELs differentiate to osteoblastic lineage after intra-marrow transplant. Importantly, VSELs from adult humans repaired a calvarial defect in SCID mice. The human VSELs formed new bone when applied in the injured area as measured by u-CT scan, and histological analysis demonstrated osteogeneis, significant new bone formation, dense thickening of the trabeculae and bone marrow formation. Most importantly, new bone tissue was derived from the human VSELs. These studies show that VSELs can generate new bone and have the potential to repair bone injuries. In this phase 2 SBIR, we propose to further test the effectiveness of human VSELs to regenerate bone in human patients. Specifically, we will test the ability of VSELs to promote bone remodeling in the human craniofacial skeleton. For our studies, we will test the efficacy of human VSELs to generate bone in humans in a tooth extraction model in which individuals requiring tooth extraction due to caries or periodontal disease will be the subjects. In these individuals, the underlying jaw bone tissue is injured and depleted and while there is some healing overtime after tooth extraction, the process is slow. We will test whether VSELs isolated from the patient expedite bone growth in the oral cavity after tooth removal. The VSELs are autologous and will not cause rejection and do not form tumors or cause other health risks. This is not a clinical trial but a focused patient based study intended to move forward the development of VSELs as a therapeutic for bone repair. It successful, these studies will provide the basis for the rapid clinical development of VSELs for craniofacial osseous regeneration and treatment of a number of other skeletal based disorders. PUBLIC HEALTH RELEVANCE: It is a goal of NeoStem to develop the therapeutic capabilities of Human VSELs to treat a host of diseases and disorders. Studies in this proposal are focused on establishing the utility of VSELs to repair bone and treat oral-craniofacial disorders. If the results of these studies in humans show safety and efficacy of adult autologous VSELs in bone repair, then we will attempt to further develop this cell therapy in clinical studies in the futureto establish the cells as a standard of care for the treatment of bone disease and loss.

描述（由申请人提供）：骨折和疾病引起的骨质流失是美国影响数百万美国人的严重病情。口头特别有问题 颅面疾病是治疗损害的费用，每年超过600亿美元。此外，牙周炎与全身性疾病有关，例如糖尿病，早产低出生体重和心血管疾病。尽管已经做出了重大努力来了解大骨骼的愈合机制并开发治疗总体骨质流失的治疗剂，但关于人类颅面骨骼的骨骼重塑的信息很少，也没有涉及颌骨骨质症的机制，几乎没有有效的治疗方法。我们第1阶段SBIR的结果表明，人类，成人，多能，非常小的胚胎（VSEL）干细胞的独特群体具有重要的骨再生特性，并且可能有助于治疗口腔颅性疾病。人类VSEL是参与组织正常周转率和组织再生及其循环水平的多能干细胞，其响应对损伤的响应大大增加。他们能够修复心肌梗塞后心脏等受伤的组织。成人人类VSEL是SSEA-4+/OCT-4+/CD133+/CXCR4+/LIN-/CD45-，Express Pluriptency标记（OCT-4和Nanog），能够与三个细菌谱系分化为细胞。与我们的合作者，密歇根大学的罗素·泰克曼（Russell Taichman）博士一起，我们表明VSELS在Marrow移植后与成骨细胞分开。重要的是，来自成年人的VSEL修复了SCID小鼠的钙钙缺陷。通过通过U-CT扫描测量的受伤区域中，人类VSEL形成了新骨，组织学分析表明骨，明显的新骨形成，小梁的密集增厚和骨髓形成。最重要的是，新的骨组织来自人类VSEL。这些研究表明，VSEL可以产生新的骨头，并具有修复骨损伤的潜力。在此阶段2 SBIR中，我们建议进一步测试人VSEL对人类患者骨骼再生的有效性。具体而言，我们将测试VSELS在人类颅面骨骼中促进骨骼重塑的能力。在我们的研究中，我们将测试人类VSEL在牙齿拔牙模型中产生骨骼的功效，在牙齿拔牙模型中，由于龋齿或牙周疾病而需要拔牙的个体将成为受试者。在这些个体中，下颌骨组织受伤和耗尽，虽然拔牙后的加班有些愈合，但过程却很慢。我们将测试从患者中分离出的VSEL是否会在清除牙齿后在口腔中加速骨骼生长。 VSEL​​是自体的，不会引起排斥，不会形成肿瘤或引起其他健康风险。这不是一项临床试验，而是一项基于重点的患者研究，旨在推动VSEL的发展作为骨修复的治疗方法。这些研究成功，这些研究将为VSEL的快速临床发展提供基础，用于颅骨再生和许多其他基于骨骼的疾病的治疗。 公共卫生相关性：Neostem的目标是发展人类VSEL的治疗能力来治疗大量疾病和疾病。该提案中的研究重点是建立VSELS修复骨骼和治疗口服颅面疾病的实用性。如果这些人类研究的结果表明了成年自体VSEL在骨修复中的安全性和功效，那么我们将尝试进一步在Futureto的临床研究中进一步开发这种细胞疗法，以建立细胞作为治疗骨骼疾病和损失的护理标准。