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首页> 外文学位 >Improving stem cell-based therapy and developing a novel gene therapy approach for treating Duchenne Muscular Dystrophy (DMD).
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Improving stem cell-based therapy and developing a novel gene therapy approach for treating Duchenne Muscular Dystrophy (DMD).

机译：改进基于干细胞的疗法，并开发一种新型的基因疗法来治疗杜兴氏肌营养不良症（DMD）。

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摘要

Genetic mutations in muscle structural genes can compromise myofiber integrity, causing repeated muscle damage that ultimately exhausts muscle regenerative capacity and results in devastating degenerative conditions such as Duchenne Muscular Dystrophy (DMD), Congenital Muscular Dystrophy (CMD) and different forms of Limb Girdle Muscular Dystrophy (LGMD). Gene supplementation and autologous stem cell transplant have been put forward as promising, though still unproven, therapeutic avenues for combatting these genetic muscle diseases. Both strategies aim to compensate expression of the missing or mutated protein. For cell therapy, autologous muscle stem cells (satellite cells) from dystrophic muscles undergo in vitro expansion and gene correction and then are transplanted into diseased tissue, where they fuse with resident myofibers to deliver a functional copy of the gene. One of the major obstacles for the autologous adult stem cell transplantation is that adult satellite cells account for a very rare population in muscle and they need to be expanded in culture, while retaining their engraftment potential, to generate sufficient number of cells for gene correction and transplantation. I tackled this problem by developing a culture condition that allows engraftable mouse satellite cells to expand in culture. This study also provides evidence for the feasibility of in vitro expansion, gene correction and transplantation of dystrophic satellite cells to restore DYSTROPHIN expression in dystrophic muscle.;In gene therapy, engineered gene products are delivered directly to muscle fibers as transgenes carried by viral vectors, such as Adeno Associated Viruses (AAVs). Viral- mediated delivery of a normal copy of the mutated genes into dystrophic muscle fibers holds big promise as a therapeutic avenue for Muscular Dystrophies. However, considering the indispensible role of satellite cells in muscle regeneration, an effective and long-term therapy for genetic muscle diseases requires restoration of gene expression in both dystrophic muscle fibers and satellite cells. Conventional gene therapy approaches lack the potential for long-term restoration of the mutated gene expression in satellite cells. In order to address this limitation, this study provides the proof of concept evidence for the use of a novel gene editing approach, which allows irreversible correction of the mutations in both dystrophic skeletal muscle fibers and satellite cells.
机译：肌肉结构基因的遗传突变会损害肌纤维的完整性，引起反复的肌肉损伤，最终耗尽肌肉的再生能力，并导致毁灭性的退化性疾病，例如杜兴氏肌营养不良（DMD），先天性肌营养不良（CMD）和不同形式的下肢腰带肌营养不良（LGMD）。已经提出了基因补充和自体干细胞移植作为有希望的，但仍未经证实的，与这些遗传性肌肉疾病作斗争的治疗途径的建议。两种策略均旨在补偿缺失或突变蛋白的表达。对于细胞治疗，来自营养不良性肌肉的自体肌肉干细胞（卫星细胞）在体外进行扩增和基因校正，然后移植到患病组织中，在其中与常驻肌纤维融合以提供功能性基因副本。自体成年干细胞移植的主要障碍之一是成年卫星细胞占肌肉中非常稀少的种群，需要在培养中扩增它们，同时保留其植入潜力，以产生足够数量的细胞用于基因校正和移植。移植。我通过开发一种培养条件解决了这个问题，该条件允许可移植的小鼠卫星细胞在培养物中扩增。这项研究也为营养不良卫星细胞的体外扩增，基因校正和移植恢复营养不良肌中DYSTROPHIN表达的可行性提供了证据。在基因治疗中，工程基因产物作为病毒载体携带的转基因直接传递给肌肉纤维，例如腺相关病毒（AAV）。病毒介导的突变基因的正常拷贝进入营养不良性肌纤维具有广阔的前景，有望作为治疗肌肉营养不良的途径。但是，考虑到卫星细胞在肌肉再生中不可或缺的作用，对遗传性肌肉疾病的有效长期治疗需要营养不良性肌纤维和卫星细胞中基因的表达恢复。传统的基因治疗方法缺乏长期恢复卫星细胞中突变基因表达的潜力。为了解决这一局限性，本研究为使用新颖的基因编辑方法提供了概念证据，该方法允许对营养不良的骨骼肌纤维和卫星细胞中的突变进行不可逆的校正。

著录项

  • 作者

    Tabebordbar, Mohammadsharif.;

  • 作者单位

    Harvard University.;

  • 授予单位 Harvard University.;
  • 学科 Genetics.;Molecular biology.;Cellular biology.
  • 学位 Ph.D.
  • 年度 2016
  • 页码 147 p.
  • 总页数 147
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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