Single non-integrating RNA vector for gene editing and reprogramming of Fanconi anemia fibroblasts

用于范可尼贫血成纤维细胞基因编辑和重编程的单一非整合RNA载体

基本信息

  • 批准号:
    10009824
  • 负责人:
  • 金额:
    $ 31.8万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-09-15 至 2020-08-31
  • 项目状态:
    已结题

项目摘要

Abstract. The recent advances in induced pluripotent stem cells (iPSCs) and gene therapy tools have opened up a new avenue to study and treat diseases, particularly of disorders with defective bone marrow. Bone marrow failure syndromes are usually marked with depleted blood cells caused due to dysfunctional bone marrow compartment. Fanconi anemia (FA) is one such bone marrow failure syndrome where cellular reprogramming is inefficient, owing to interference of the disease-related genes. To overcome this limitation, it is necessary to fundamentally correct the abnormal gene (e.g.: FANCD1) during or prior to the reprogramming process. In the past, obtaining genetically modified iPSC from the fibroblasts of these patients typically involved multiple steps. But recent progress in the field has paved way for simultaneous reprogramming and gene targeting in a single step using multiple episomal vectors. In this study we propose to take the multiple vector-single step procedure to single vector-single step approach to obtain corrected iPSC from FA fibroblasts. Our single vector is based on a non-integrating negative strand RNA virus, Measles virus (MV). The central hypothesis is that a MV vectors can be designed to express all components in one genome, and lead to the generation of clinically safe, corrected and functional iPSCs from FA fibroblasts. The rationale for the proposed research is that the “one-cycle” MV vector, MV4F, expressing the four reprogramming factors, generate iPSC from human fibroblasts and is quickly diluted and eliminated from the iPSC after reprogramming. Guided by strong preliminary data, the specific aim of this particular application is to produce a one-cycle “all-in-one” MV vectors, containing the four reprogramming factors plus Cas9-gRNA, and setup the protocol for concurrently reprogram and edit the genome of human fibroblasts carrying a genetic mutation. The proposed work is innovative, because it capitalizes on a new technology that relies on one single vector expressing the four reprogramming factors (RFs) for the reprogramming of somatic cells into iPSC; and our group developed that technology. Finally, the corrected iPSC will be tested for there ability to differentiated into hematopoietic stem cells. The proposed work is significant because develop a new single vector for the production corrected iPSC, that will be eliminated quickly form the established iPSC and that can be translated into the clinic quickly, as it based on the safe measles vaccine strain. Finally, the proposed research is relevant to that part of NIH's mission that pertains to develop new treatments for Inherited Bone Marrow failure syndromes, haemoglobinopathies, immunodeficiencies, and other monogenetic disorders to reduce the burden of human disease.
抽象。 诱导多能干细胞(iPSC)和基因治疗工具的最新进展开辟了一个新的领域。 研究和治疗疾病的途径,特别是有缺陷的骨髓疾病。骨髓衰竭 综合征通常以由于骨髓功能障碍引起的血细胞耗竭为标志, 车厢范可尼贫血(FA)是一种骨髓衰竭综合征, 由于疾病相关基因的干扰,为了克服这一限制,必须 从根本上纠正异常基因(例如:FANCD 1)在重编程过程期间或之前。在 过去,从这些患者的成纤维细胞获得遗传修饰的iPSC通常涉及多个步骤。 但该领域的最新进展为同时进行重编程和基因靶向铺平了道路, 步骤使用多个附加型载体。在这项研究中,我们建议采取多向量单步程序 至单载体-单步方法以从FA成纤维细胞获得校正的iPSC。我们的单个向量基于 非整合负链RNA病毒麻疹病毒(MV)。核心假设是MV 载体可以被设计为在一个基因组中表达所有组分,并导致临床上的 来自FA成纤维细胞的安全、校正和功能性iPSC。拟议研究的理由是, 表达四种重编程因子的“单循环”MV载体MV 4F从人类产生iPSC, iPSC是成纤维细胞的细胞,并且在重编程后迅速稀释并从iPSC中消除。以强为导 根据初步数据,该特定应用的具体目的是产生单循环“一体化”MV载体, 包含四种重编程因子加上Cas9-gRNA,并建立用于同时重编程的方案 并编辑携带基因突变的人类成纤维细胞的基因组。拟议的工作是创新的, 因为它利用了一种新技术,这种技术依赖于一个单一的载体, 将体细胞重编程为iPSC的因子(RFs);我们的团队开发了这项技术。 最后,将测试校正的iPSC分化成造血干细胞的能力。的 拟议的工作是重要的,因为开发一个新的单一载体的生产纠正iPSC,这将 从已建立的iPSC中快速消除,并且可以快速转化为临床,因为它基于 安全的麻疹疫苗株最后,拟议的研究与NIH的使命的一部分有关, 属于开发新的治疗遗传性骨髓衰竭综合征,血红蛋白病, 免疫缺陷和其他单基因疾病,以减少人类疾病的负担。

项目成果

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Patricia DEVAUX其他文献

Patricia DEVAUX的其他文献

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{{ truncateString('Patricia DEVAUX', 18)}}的其他基金

Single non-integrating RNA vector for gene editing and reprogramming of Fanconi anemia fibroblasts
用于范可尼贫血成纤维细胞基因编辑和重编程的单一非整合RNA载体
  • 批准号:
    10462485
  • 财政年份:
    2020
  • 资助金额:
    $ 31.8万
  • 项目类别:
Measles virus as a tool for iPSC-independent tissue specific reprogramming
麻疹病毒作为独立于 iPSC 的组织特异性重编程工具
  • 批准号:
    8966897
  • 财政年份:
    2015
  • 资助金额:
    $ 31.8万
  • 项目类别:
Measles vectors for genomic modification-free induced pluripotent stem cells
用于无基因组修饰诱导多能干细胞的麻疹载体
  • 批准号:
    8605520
  • 财政年份:
    2013
  • 资助金额:
    $ 31.8万
  • 项目类别:
Measles vectors for genomic modification-free induced pluripotent stem cells
用于无基因组修饰诱导多能干细胞的麻疹载体
  • 批准号:
    8488790
  • 财政年份:
    2013
  • 资助金额:
    $ 31.8万
  • 项目类别:
Control of innate immunity and apoptosis by Measles virus P, V and C proteins
麻疹病毒 P、V 和 C 蛋白控制先天免疫和细胞凋亡
  • 批准号:
    7629786
  • 财政年份:
    2008
  • 资助金额:
    $ 31.8万
  • 项目类别:
Control of innate immunity and apoptosis by Measles virus P, V and C proteins
麻疹病毒 P、V 和 C 蛋白控制先天免疫和细胞凋亡
  • 批准号:
    7352405
  • 财政年份:
    2008
  • 资助金额:
    $ 31.8万
  • 项目类别:

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