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Engineering gene delivery vectors through genetic and conjugational modifications.

机译：通过遗传和共轭修饰来工程化基因传递载体。

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摘要

The greatest obstacle to gene therapy lies in development of efficient gene delivery vectors. Currently, the most efficient vectors are derived from viruses. Even though viruses have, over millions of years, evolved to become very efficient at delivering genes as part of their life cycles, their gene transfer properties are not necessary optimized for therapeutic application. In addition, research in the past two decades had made apparent that there is not a "magical" gene delivery system that is suitable for all applications. Therefore, recent efforts have emphasized tailoring of specific viral vectors to satisfy particular therapeutic needs. The efficiency of gene delivery vectors is greatly dependent on overcoming certain barriers to the gene transfer process, and the goal of this research is to engineer specific properties into viral vectors to circumvent key gene delivery barriers.;Alleviating transcriptional silencing of MoMLV in mouse stem cells. The combined application of gene therapy and stem cell engineering for tissue regeneration has recently drawn immense interest. In recent clinical trials, several patients who suffered from different forms of severe combined immunodeficiency syndrome (SCID) were treated with Moloney Murine Leukemia (MoMLV) vectors in which corrective genes were introduced into the patients' blood stem cells. This marked the first successful cure in a gene therapy clinical trial. However, the vectors require further engineering to improve the gene expression and safety of retroviral gene delivery to stem cells. Among their limitations, MoMLV vectors suffer from transcriptional silencing in many stem cells, both in vitro and in vivo. Enhancing gene expression after vector delivery could improve therapeutic efficacy, as well as improve safety by lowering the necessary dosage. So far, five different regions within the retroviral genome have been identified as recognized targets that promote silencing, and most of which lie within the U3 region of the viral Long Terminal Repeat (LTR). The effect of silencing can be reduced by modification and/or deletions of these regions; however, complete relief has never been achieved. Furthermore, improvements in long-term expression by these LTR modifications usually come at the cost of significant reductions in vector production and infectivity. (Abstract shortened by UMI.).
机译：基因治疗的最大障碍在于开发有效的基因传递载体。当前，最有效的载体源自病毒。即使病毒已经发展了数百万年，已成为在生命周期中传递基因的非常有效的方法，但它们的基因转移特性并不需要针对治疗应用进行优化。另外，过去二十年的研究表明，没有一种适用于所有应用的“神奇”基因传递系统。因此，最近的努力强调了对特定病毒载体的定制以满足特定的治疗需要。基因传递载体的效率在很大程度上取决于克服基因传递过程中的某些障碍，这项研究的目标是将特定特性改造成病毒载体，从而规避关键的基因传递障碍。减轻小鼠干细胞中MoMLV的转录沉默。 。基因疗法和干细胞工程技术用于组织再生的结合应用最近引起了极大的兴趣。在最近的临床试验中，使用莫洛尼鼠白血病（MoMLV）载体治疗了几例患有不同形式的严重合并免疫缺陷综合症（SCID）的患者，其中将校正基因引入了患者的血液干细胞中。这标志着基因疗法临床试验中第一个成功的治愈方法。然而，载体需要进一步的工程改造以改善基因表达和逆转录病毒基因递送至干细胞的安全性。在它们的局限性中，MoMLV载体在体外和体内都在许多干细胞中遭受转录沉默。载体递送后增强基因表达可以提高治疗效果，并通过降低必要的剂量来提高安全性。迄今为止，逆转录病毒基因组中的五个不同区域已被识别为促进沉默的靶标，其中大多数位于病毒长末端重复序列（LTR）的U3区域内。可以通过修饰和/或删除这些区域来降低沉默的影响。但是，从未实现完全的缓解。此外，通过这些LTR修饰来改善长期表达通常以显着降低载体产量和感染性为代价。 （摘要由UMI缩短。）。

著录项

  • 作者

    Lee, Gary Ka Leong.;

  • 作者单位

    University of California, Berkeley.;

  • 授予单位 University of California, Berkeley.;
  • 学科 Chemical engineering.
  • 学位 Ph.D.
  • 年度 2004
  • 页码 156 p.
  • 总页数 156
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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