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
基本信息
- 批准号:8394099
- 负责人:
- 金额:$ 41.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Absorbable Gelatin SpongeAdultAffectAftercareAmericanAnimalsAntibodiesApoptosisAreaAssesAutologousBicuspidBiopsyBloodBlood Component RemovalBone DiseasesBone GrowthBone InjuryBone MarrowBone Marrow AspirationBone RegenerationBone ResorptionBone TissueBone necrosisBone remodelingCXCR4 geneCalciumCalvariaCardiovascular DiseasesCell TherapyCellsClinicalClinical ResearchClinical TrialsCollaborationsColorCyclophosphamideDefectDental ImplantsDental cariesDevelopmentDiabetes MellitusDiseaseDouble-Blind MethodEffectivenessEmbryoEnrollmentEthicsEvaluationExcisionFluorescenceFractureFutureGermGoalsGrantHealedHealthHeartHumanImmunohistochemistryImplantation procedureIn VitroIndividualInjuryJawLabelLeftLong-Term EffectsLow Birth Weight InfantMandibleMarrowMaxillaMeasuresMedicalMichiganModelingMyocardial InfarctionNatural regenerationOralOral cavityOsteoblastsOsteogenesisPTPRC genePatientsPeriodontal DiseasesPeriodontitisPhasePlacebosPluripotent Stem CellsPopulationProceduresProcessPropertyRandomizedReconstructive Surgical ProceduresRiskSCID MiceSafetyScheduleSerumSerum MarkersSiteSkeletonSmall Business Innovation Research GrantStem cellsStructureTechniquesTestingTetracyclinesTherapeuticTimeTissuesTooth ExtractionTooth SocketTooth structureTransplantationUniversitiesX-Ray Computed Tomographybasebonebone healingbone losscostcraniofacialeffective therapyeffectiveness measureefficacy testinggraft vs host diseasehealingimprovedin vivoinjuredosteogenicpluripotencyreconstructionregenerativerepairedresponse to injuryskeletalstage-specific embryonic antigen 4standard of carestem cell therapysuccesstissue regenerationtissue repairtreatment sitetumor
项目摘要
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):在美国,由于骨折和疾病导致的骨丢失是一种严重的医疗状况,影响着数百万美国人。这是一个特别的问题,
颅面疾病的治疗费用每年超过600亿美元。此外,牙周炎与全身性疾病如糖尿病、早产低出生体重和心血管疾病有关。虽然已经做出了重大努力来了解大骨愈合的机制,并开发治疗方法来治疗整体骨丢失,但关于人类颅面骨骼中骨重建的信息非常少,也没有涉及颌骨骨坏死的机制,并且几乎没有有效的治疗方法。我们的1期SBIR的结果表明,一个独特的人类,成人,多能,非常小的胚胎样(VSEL)干细胞群体,具有重要的骨再生特性,可用于治疗口腔颅面疾病。人VSEL是参与组织正常周转和再生的多能干细胞,并且其循环水平响应于损伤而大大增加。它们能够修复受损的组织,如心肌梗死后的心脏。成人VSEL是SSEA-4+/Oct-4+/CD 133 +/CXCR 4 +/Lin-/CD 45-,表达多能性标志物(Oct-4和Nanog),并且能够分化成来自所有三种生殖谱系的细胞。与我们的合作者,密歇根大学的Russell Taichman博士一起,我们证明了骨髓内移植后VSELs分化为成骨细胞谱系。重要的是,来自成年人的VSELs修复了SCID小鼠的颅骨缺陷。当应用于损伤区域时,如通过u-CT扫描测量的,人VSEL形成新骨,并且组织学分析显示成骨、显著的新骨形成、骨小梁致密增厚和骨髓形成。最重要的是,新的骨组织来源于人VSEL。这些研究表明,VSELs可以生成新骨,并具有修复骨损伤的潜力。在这个2期SBIR中,我们建议进一步测试人VSEL在人类患者中再生骨的有效性。具体来说,我们将测试VSELs促进人类颅面骨骼骨重建的能力。对于我们的研究,我们将在拔牙模型中测试人VSEL在人体中生成骨的功效,其中由于龋齿或牙周病需要拔牙的个体将是受试者。在这些人中,下面的颌骨组织受伤和耗尽,虽然拔牙后有一些愈合时间,但这个过程很慢。我们将测试从患者体内分离的VSELs是否会加速牙齿拔除后口腔中的骨生长。VSEL是自体的,不会引起排斥反应,也不会形成肿瘤或引起其他健康风险。这不是一项临床试验,而是一项基于患者的重点研究,旨在推动VSEL作为骨修复治疗药物的开发。如果成功,这些研究将为VSELs用于颅面骨再生和治疗许多其他骨骼疾病的快速临床开发提供基础。
公共卫生相关性:NeoStem的目标是开发人类VSEL的治疗能力,以治疗多种疾病和病症。该提案中的研究重点是建立VSEL修复骨和治疗口腔颅面疾病的实用性。如果这些人体研究的结果显示成人自体VSEL在骨修复中的安全性和有效性,那么我们将尝试在未来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疾病和损失的标准护理。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Laurie K. McCauley其他文献
Effects of transforming growth factor-α on parathyroid hormone- and parathyroid hormone-related protein- mediated bone resorption and adenylate cyclase stimulation in vitro☆
转化生长因子-α对甲状旁腺激素及甲状旁腺激素相关蛋白介导的骨吸收和体外腺苷酸环化酶刺激的影响☆
- DOI:
10.1016/0739-7240(91)90019-g - 发表时间:
1991 - 期刊:
- 影响因子:2.1
- 作者:
T. Rosol;J. Merryman;R. Nohutçu;Laurie K. McCauley;C. Capen - 通讯作者:
C. Capen
Skeletal metastasis: Established and emerging roles of parathyroid hormone related protein (PTHrP)
- DOI:
10.1007/s10555-006-9033-z - 发表时间:
2006-12-13 - 期刊:
- 影响因子:8.700
- 作者:
Jinhui Liao;Laurie K. McCauley - 通讯作者:
Laurie K. McCauley
Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism: Seventh Edition
代谢性骨疾病和矿物质代谢紊乱入门:第七版
- DOI:
10.1002/9780470623992 - 发表时间:
2009 - 期刊:
- 影响因子:3.4
- 作者:
Clifford J. Rosen;J. Compston;J. Lian;R. Bouillon;S. J. Beur;S. Papapoulos;Pierre D. Delmas;Richard Keen;Vicki Rosen;M. Demay;Laurie K. McCauley;Ego Seeman;T. Guise;Paul D. Miller;R. V. Thakker - 通讯作者:
R. V. Thakker
Prostate Carcinoma Skeletal Metastases: Cross-talk between Tumor and Bone
- DOI:
10.1023/a:1015599831232 - 发表时间:
2001-12-01 - 期刊:
- 影响因子:8.700
- 作者:
Evan T. Keller;Jian Zhang;Carlton R. Cooper;Peter C. Smith;Laurie K. McCauley;Kenneth J. Pienta;Russell S. Taichman - 通讯作者:
Russell S. Taichman
Laurie K. McCauley的其他文献
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{{ truncateString('Laurie K. McCauley', 18)}}的其他基金
Integral role of hematopoietic cells in PTH actions in bone
造血细胞在骨 PTH 作用中的整体作用
- 批准号:
7684217 - 财政年份:2008
- 资助金额:
$ 41.18万 - 项目类别:
Integral role of hematopoietic cells in PTH actions in bone
造血细胞在骨 PTH 作用中的整体作用
- 批准号:
7556574 - 财政年份:2008
- 资助金额:
$ 41.18万 - 项目类别:
Integral role of hematopoietic cells in PTH actions in bone
造血细胞在骨 PTH 作用中的整体作用
- 批准号:
7932543 - 财政年份:2008
- 资助金额:
$ 41.18万 - 项目类别:
IMPACT OF PARATHYROID HORMONE (1-34) ON OSSEOUS REGENERATION IN THE ORAL CAVITY
甲状旁腺激素 (1-34) 对口腔骨再生的影响
- 批准号:
7603775 - 财政年份:2007
- 资助金额:
$ 41.18万 - 项目类别:
IMPACT OF PARATHYROID HORMONE (1-34) ON OSSEOUS REGENERATION IN THE ORAL CAVITY
甲状旁腺激素 (1-34) 对口腔骨再生的影响
- 批准号:
7199936 - 财政年份:2005
- 资助金额:
$ 41.18万 - 项目类别:
PTHrP, Osteoblasts and Hematopoietic Cells in the Sketletal Metastic Niche
骨骼转移微环境中的 PTHrP、成骨细胞和造血细胞
- 批准号:
8377423 - 财政年份:2004
- 资助金额:
$ 41.18万 - 项目类别:
PTHrP, Osteoblasts and Hematopoietic Cells in the Sketletal Metastic Niche
骨骼转移微环境中的 PTHrP、成骨细胞和造血细胞
- 批准号:
7659015 - 财政年份:2004
- 资助金额:
$ 41.18万 - 项目类别:
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