摘要
在过去的几年中,已有研究成功通过 gammaretro病毒或者慢病毒的载体系统转移了治疗性基因。这证明了携带这些基因的病毒可以作为治疗一系列遗传疾病的可选方法。基因疗法已批准的I / II期临床试验的数量,特别是罕见病的,正稳步上升,但要成为被广泛接受的治疗方法整体上仍然存在众多障碍。在临床医生和基础科研人员的努力下,我们对基因治疗的可行性和生物安全性的认识提高到了新的水平。然而,尽管已产生了大量的临床和临床前安全性数据,我们还缺乏足够强有力的检测,以评估预测在临床基因治疗中将遇到的确切水平。插入诱变是使用整合载体永久改造细胞时的主要问题之一;而在早期基因治疗试验中与基因毒性相关的不良事件的发生,都抑制了基因治疗领域的进一步发展。在本综述中, 我们总结了已报道的使用整合载体进行基因治疗的临床试验中发生的不良事件,全面概述了其中共有的基本原则和潜在的共同因素。此外,我们总结了在临床前水平下可用以评估遗传毒性的系统,并揭示了在临床角度下解释这些毒性研究结果时影响这些试验预测值的问题。在综述的最后一节,我们简要介绍了未来的发展趋势,以及未来趋势如何能提高采用整合载体技术的基因疗法的安全性,并使其发展到一个新的水平。
关键词: 临床试验、基因疗法、插入诱变、慢病毒载体的、临床前的、逆转录病毒的、安全性。
Current Gene Therapy
Title:Safety of Gene Therapy: New Insights to a Puzzling Case
Volume: 14 Issue: 6
Author(s): Michael Rothe, Axel Schambach and Luca Biasco
Affiliation:
关键词: 临床试验、基因疗法、插入诱变、慢病毒载体的、临床前的、逆转录病毒的、安全性。
摘要: Over the last few years, the transfer of therapeutic genes via gammaretro- or lentiviral vector systems has proven its virtue as an alternative treatment for a series of genetic disorders. The number of approved phase I/II clinical trials, especially for rare diseases, is steadily increasing, but the overall hurdles to become a broadly acceptable therapy remain numerous. The efforts by clinicians and basic scientists have tremendously improved the knowledge available about feasibility and biosafety of gene therapy. Nonetheless, despite the generation of a plethora of clinical and preclinical safety data, we still lack sufficiently powerful assays to predictively assess the exact levels of toxicity that might be observed in any given clinical gene therapy. Insertional mutagenesis is one of the major concerns when using integrating vectors for permanent cell modification, and the occurrence of adverse events related to genotoxicity, in early gene therapy trials, has refrained the field of gene therapy from emerging further. In this review, we provided a comprehensive overview on the basic principles and potential co-factors concurring in the generation of adverse events reported in gene therapy clinical trials using integrating vectors. Additionally, we summarized the available systems to assess genotoxicity at the preclinical level and we shed light on the issues affecting the predictive value of these assays when translating their results into the clinical arena. In the last section of the review we briefly touched on the future trends and how they could increase the safety of gene therapy employing integrating vector technology to take it to the next level.
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Cite this article as:
Rothe Michael, Schambach Axel and Biasco Luca, Safety of Gene Therapy: New Insights to a Puzzling Case, Current Gene Therapy 2014; 14 (6) . https://dx.doi.org/10.2174/1566523214666140918110905
DOI https://dx.doi.org/10.2174/1566523214666140918110905 |
Print ISSN 1566-5232 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5631 |
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