GENE TARGETING STRATEGIES FOR THE TREATMENT OF OSTEOGENESIS IMPERFECTA
治疗成骨不全的基因靶向策略
基本信息
- 批准号:7827085
- 负责人:
- 金额:$ 42.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-09-25 至 2012-09-24
- 项目状态:已结题
- 来源:
- 关键词:Autologous TransplantationBiological AssayCOL1A1 geneCOL1A2 geneCellsCessation of lifeCollagenCollagen GeneDependovirusEngraftmentFractureFundingGene MutationGene TargetingGenesGenetic PolymorphismGenetic RecombinationHereditary DiseaseHydroxyapatitesImmunodeficient MouseIndividualLentivirus VectorLong Terminal RepeatsMeasuresMediatingMesenchymalMesenchymal Stem CellsMessenger RNAModelingMutationOryctolagus cuniculusOsteoblastsOsteogenesisOsteogenesis ImperfectaPatientsPeptidesPhenotypePluripotent Stem CellsPolyproteinsProductionProteinsProvirusesRecoveryResidual stateRetroviral VectorSiteSpumavirusTherapeuticTransgenesTransplantationUnited States National Institutes of Healthadeno-associated viral vectorbasebonedesigndisease-causing mutationimprovedin vivoinduced pluripotent stem cellmutantnovel therapeuticsprematurepublic health relevancerecombinaseresearch studyresponseskeletal abnormalitytransgene expressiontreatment strategytricalcium phosphatevector
项目摘要
DESCRIPTION (provided by applicant): This is a competitive revision application for R01 AR048328 in response to NIH Notice NOT-OD-09- 058: "NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications". Osteogenesis Imperfecta (OI) is a genetic disease caused by mutations in the type I collagen genes COL1A1 or COL1A2 that can result in major skeletal abnormalities, fractures, and premature death. We showed previously that gene targeting vectors based on adeno-associated virus (AAV) can efficiently disrupt mutant COL1A1 and COL1A2 genes in mesenchymal stem cells (MSCs) from individuals with OI, and that these MSCs then produced normal collagen and formed bone. In this R01, we received funding for three specific aims: to develop improved AAV vectors that target mutant collagen genes, to determine the effects of genetic polymorphisms on targeting, and to transplant MSCs and measure engraftment using a rabbit model. These Aims are intended to develop a therapeutic strategy consisting of isolation of a patient's MSCs, gene targeting to eliminate the mutant collagen gene, and transplantation of these autologous, targeted MSCs. While this remains a promising approach, its major shortcoming is the number of MSCs that can be obtained during ex vivo expansion. In this competitive revision application we propose to overcome this potential limitation by deriving induced pluripotent stem cells (iPSCs) from OI MSCs, which are immortal and capable of differentiating into MSCs and forming bone in vivo. We will derive iPSCs from OI MSCs, correct the collagen mutations in them by AAV-mediated gene targeting, and demonstrate these iPSCs can still form bone.
PUBLIC HEALTH RELEVANCE: These experiments are meant to develop a new therapeutic paradigm, in which patient-specific pluripotent stem cells (iPSCs) are corrected by gene targeting and then returned to the patient. They will establish the feasibility of correcting genetic mutations in iPSCs and using these cells to generate bone, with major significance for the treatment of genetic diseases such as osteogenesis imperfecta.
描述(由申请人提供):这是R 01 AR 048328的竞争性修订申请,以响应NIH通知NOT-OD-09- 058:“NIH宣布恢复法案资金可用于竞争性修订申请”。成骨不全症(OI)是一种由I型胶原基因COL 1A 1或COL 1A 2突变引起的遗传性疾病,可导致严重的骨骼异常、骨折和过早死亡。我们先前表明,基于腺相关病毒(AAV)的基因靶向载体可以有效地破坏来自OI个体的间充质干细胞(MSC)中的突变COL 1A 1和COL 1A 2基因,然后这些MSC产生正常的胶原蛋白并形成骨。在R 01中,我们获得了三个具体目标的资金:开发针对突变型胶原基因的改进的AAV载体,确定遗传多态性对靶向的影响,以及移植MSC并使用兔模型测量植入。这些目标旨在开发一种治疗策略,包括分离患者的MSC,基因靶向以消除突变型胶原基因,以及移植这些自体靶向MSC。虽然这仍然是一种有前途的方法,但其主要缺点是在离体扩增期间可以获得的MSC的数量。在这种竞争性的修订申请中,我们提出通过从OI MSC中获得诱导多能干细胞(iPSC)来克服这种潜在的限制,所述诱导多能干细胞是永生的并且能够分化成MSC并在体内形成骨。我们将从OI MSC中获得iPSC,通过AAV介导的基因靶向纠正其中的胶原突变,并证明这些iPSC仍然可以形成骨。
公共卫生关系:这些实验旨在开发一种新的治疗模式,其中患者特异性多能干细胞(iPSC)通过基因靶向进行校正,然后返回患者体内。他们将确定纠正iPSC中的基因突变并使用这些细胞生成骨骼的可行性,这对治疗遗传性疾病如骨生成障碍具有重要意义。
项目成果
期刊论文数量(0)
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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David W Russell其他文献
Adeno-associated virus finds its disease
腺相关病毒找到其疾病
- DOI:
10.1038/ng.3407 - 发表时间:
2015-09-29 - 期刊:
- 影响因子:29.000
- 作者:
David W Russell;Markus Grompe - 通讯作者:
Markus Grompe
A Genome-Wide Map of AAV-Mediated Human Gene Targeting
AAV 介导的人类基因靶向的全基因组图谱
- DOI:
- 发表时间:
2014 - 期刊:
- 影响因子:0
- 作者:
D. Deyle;R. S. Hansen;A. Cornea;Li B Li;Amber A Burt;Ian E Alexander;R. Sandstrom;J. Stamatoyannopoulos;Chia;David W Russell - 通讯作者:
David W Russell
David W Russell的其他文献
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{{ truncateString('David W Russell', 18)}}的其他基金
American Society of Gene & Cell Therapy (ASGCT) 17th Annual Meeting
美国基因学会
- 批准号:
8720363 - 财政年份:2014
- 资助金额:
$ 42.9万 - 项目类别:
Derivation and Correction of Thalassemic Pluripotent Stem Cells
地中海贫血多能干细胞的衍生和校正
- 批准号:
7799411 - 财政年份:2009
- 资助金额:
$ 42.9万 - 项目类别:
Derivation and Transplantation of Histocompatible Pluripotent Stem Cells
组织相容性多能干细胞的衍生和移植
- 批准号:
7924653 - 财政年份:2009
- 资助金额:
$ 42.9万 - 项目类别:
Treatment of Leukocyte Adhesion Deficiency by Foamy Virus Vectors
泡沫病毒载体治疗白细胞粘附缺陷
- 批准号:
7265259 - 财政年份:2006
- 资助金额:
$ 42.9万 - 项目类别:
Treatment of Leukocyte Adhesion Deficiency by Foamy Virus Vectors
泡沫病毒载体治疗白细胞粘附缺陷
- 批准号:
8256628 - 财政年份:2006
- 资助金额:
$ 42.9万 - 项目类别:
Treatment of Leukocyte Adhesion Deficiency by Foamy Virus Vectors
泡沫病毒载体治疗白细胞粘附缺陷
- 批准号:
7467903 - 财政年份:2006
- 资助金额:
$ 42.9万 - 项目类别:
Treatment of Leukocyte Adhesion Deficiency by Foamy Virus Vectors
泡沫病毒载体治疗白细胞粘附缺陷
- 批准号:
7653645 - 财政年份:2006
- 资助金额:
$ 42.9万 - 项目类别:
Treatment of Leukocyte Adhesion Deficiency by Foamy Virus Vectors
泡沫病毒载体治疗白细胞粘附缺陷
- 批准号:
8391684 - 财政年份:2006
- 资助金额:
$ 42.9万 - 项目类别:
Treatment of Leukocyte Adhesion Deficiency by Foamy Virus Vectors
泡沫病毒载体治疗白细胞粘附缺陷
- 批准号:
8591396 - 财政年份:2006
- 资助金额:
$ 42.9万 - 项目类别:
Treatment Leukocyte Adhesion Deficiency by Foamy Virus
泡沫病毒治疗白细胞粘附缺陷
- 批准号:
7128279 - 财政年份:2006
- 资助金额:
$ 42.9万 - 项目类别:
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