Lentiviral Gene Therapy of X-linked Agammaglobulinemia
X连锁无丙种球蛋白血症的慢病毒基因治疗
基本信息
- 批准号:7092181
- 负责人:
- 金额:$ 37.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-08-01 至 2009-07-31
- 项目状态:已结题
- 来源:
- 关键词:B lymphocyteLentivirusNOD mouseSCID mouseclinical researchgene expressiongene therapygenetically modified animalshematopoietic stem cellshuman subjecthypogammaglobulinemialaboratory mousenonhuman therapy evaluationprotein tyrosine kinasesex linked traitstem cell transplantationtherapy design /developmenttransfection /expression vectorvirus integration
项目摘要
DESCRIPTION (provided by applicant): X-linked agammaglobulinemia (XLA) results from deficient function of Bruton's tyrosine kinase (Btk) and is characterized by a severe block in early B-cell development. The selective pressure for B cells expressing normal Btk suggests that introduction of a normal Btk cDNA into autologous hematopoietic stem cells (HSC) may lead to long-term immunologic reconstitution in XLA. Using onco-retroviral vectors optimized for murine HSC expression and transplantation of transduced stem cells into Btk/Tec doubly deficient recipients we have recently achieved: full rescue of both primary and peripheral Btk-dependent B-cell development, and correction of B cell functional responses. This data demonstrates that Btk gene transfer can reconstitute Btk-dependent functions in an animal model of XLA, and strongly support the further pursuit of this therapeutic approach. The current proposal seeks to address several key issues required to move forward with development of a definitive XLA genetic therapy including development of lentiviral vectors that: mediate highly efficient Btk gene delivery into human HSC; specifically target Btk expression to B lineage cells; and exhibit a significantly reduced risk of viral enhancer mediated mutagenesis proximal to the sited of viral integration. We will test the hypotheses that: 1) Lentiviral vectors containing B-lineage specific promoter/enhancers will mediate sustained, temporally appropriate levels Btk gene expression and lead to rescue of B cell function in vivo and in vitro; and that 2) Incorporation of an insulator elements into these vectors will promote both improved expression and, more importantly, a significantly reduced risk for of viral enhancer mutagenesis. Recent clinical trials for primary immunodeficiency disorders highlight the great potential for genetic correction as well as an unanticipated, high risk for development of onco-retroviral associated malignancies. While conceptually simple, implementation of definitive genetic therapy in XLA will require a concerted program of basic and applied research aimed at developing safe and efficient vector systems capable of appropriate, specific, and sustained B lineage gene expression. Overcoming these technical challenges should also provide insight for development of gene therapy in congenital diseases that lack a selective advantage.
描述(由申请方提供):X连锁无丙种球蛋白血症(XLA)由布鲁顿酪氨酸激酶(Btk)功能缺陷引起,特征为早期B细胞发育严重阻滞。表达正常Btk的B细胞的选择压力表明,将正常Btk cDNA引入自体造血干细胞(HSC)中可能导致XLA中的长期免疫重建。使用优化用于鼠HSC表达的肿瘤逆转录病毒载体和将转导的干细胞移植到Btk/Tec双缺陷受体中,我们最近实现了:完全拯救原发性和外周Btk依赖性B细胞发育,并校正B细胞功能反应。这些数据表明,Btk基因转移可以重建XLA动物模型中的Btk依赖性功能,并强烈支持进一步追求这种治疗方法。目前的建议旨在解决几个关键问题,需要向前发展的一个明确的XLA基因治疗,包括开发慢病毒载体:介导高效的Btk基因递送到人HSC;特异性靶向Btk表达到B谱系细胞;并表现出显着降低的风险,病毒增强子介导的诱变病毒整合的位点附近。我们将测试以下假设:1)含有B系特异性启动子/增强子的慢病毒载体将介导持续的、时间上适当水平的Btk基因表达,并导致体内和体外B细胞功能的拯救;以及2)将绝缘子元件并入这些载体将促进表达的改善,更重要的是,显著降低病毒增强子诱变的风险。最近的原发性免疫缺陷疾病的临床试验突出了遗传校正的巨大潜力,以及肿瘤逆转录病毒相关恶性肿瘤发展的意外高风险。虽然概念上简单,但XLA中确定性基因治疗的实施将需要基础和应用研究的协调计划,旨在开发能够适当、特异和持续表达B谱系基因的安全有效的载体系统。克服这些技术挑战也应该为缺乏选择性优势的先天性疾病的基因治疗的发展提供见解。
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)
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David J Rawlings其他文献
Partially Mismatched Cord Blood Transplantation In X-Linked Immunodeficiencies • 44
部分不匹配的脐带血移植在 X 连锁免疫缺陷病中的应用•44
- DOI:
10.1203/00006450-199804001-00065 - 发表时间:
1998-04-01 - 期刊:
- 影响因子:3.100
- 作者:
E Richard Stiehm;Ulrike Ziegner;Sunisa Dovat;Mary Wakim;Maria Garcia-Lloret;Hans Ochs;Kerry Gallagher;Thomas Gross;David J Rawlings;Robert L Roberts;Stephen A Feig - 通讯作者:
Stephen A Feig
An exemplum of XLA.
XLA 的一个例子。
- DOI:
- 发表时间:
2008 - 期刊:
- 影响因子:8.6
- 作者:
L. Notarangelo;David J Rawlings;K. Sullivan - 通讯作者:
K. Sullivan
David J Rawlings的其他文献
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{{ truncateString('David J Rawlings', 18)}}的其他基金
An integrated strategy to define the functional and synergistic impact of T1D causal variants
定义 T1D 因果变异的功能和协同影响的综合策略
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9227381 - 财政年份:2016
- 资助金额:
$ 37.84万 - 项目类别:
Lentiviral Gene Therapy of X-Linked Agammaglobulinemia
X连锁无丙种球蛋白血症的慢病毒基因治疗
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B cell function and phenotype as predictors of therapeutic response to rituximab
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7576150 - 财政年份:2008
- 资助金额:
$ 37.84万 - 项目类别:
Lentiviral Gene Therapy for Wiskott-Aldrich Syndrome
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7463332 - 财政年份:2008
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Lentiviral Gene Therapy for Wiskott-Aldrich Syndrome
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- 批准号:
8228037 - 财政年份:2008
- 资助金额:
$ 37.84万 - 项目类别:
Lentiviral Gene Therapy for Wiskott-Aldrich Syndrome
威斯科特-奥尔德里奇综合征的慢病毒基因治疗
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7772315 - 财政年份:2008
- 资助金额:
$ 37.84万 - 项目类别:
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威斯科特-奥尔德里奇综合征的慢病毒基因治疗
- 批准号:
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