Nat Chem Biol:消灭肿瘤细胞!新型基因疗法问世!

2018-10-21 Michael,Zoe 转化医学网

目前随着基因测序技术以及CRISPR-Cas9等基因编辑技术的发展,越来越多的遗传疾病的治疗不再是“天方夜谭”。虽然各项技术的发展给与遗传病的临床治疗莫大帮助,但MIT的研究人员并不止步于基于DNA编辑技术的基因疗法。目前,来自MIT Tasuku Kitada教授的研究团队开发出一种基于RNA的新型基因治疗技术。其最新的研究成果发表于近期的《Nature Chemical Biology》。

目前随着基因测序技术以及CRISPR-Cas9等基因编辑技术的发展,越来越多的遗传疾病的治疗不再是“天方夜谭”。虽然各项技术的发展给与遗传病的临床治疗莫大帮助,但MIT的研究人员并不止步于基于DNA编辑技术的基因疗法。目前,来自MIT Tasuku Kitada教授的研究团队开发出一种基于RNA的新型基因治疗技术。其最新的研究成果发表于近期的《Nature Chemical Biology》。

基于RNA环的新基因治疗方法可允许RNA转录物的表达由人工植入的小分子药物控制。这种RNA环可以使临床医生能够对患者体内所产生治疗性蛋白质的剂量进行调整。与基于RNA的基因疗法相比,基于DNA的基因疗法(通常的基因疗法)很难在哺乳动物中难以实现。

新的DNA必须被纳米颗粒或病毒载体运输后才能被运送入细胞核,这可能导致植入的DNA产生免疫原性或转运效率低下。但当新DNA进入细胞核,其便可控制整个靶基因的转录表达。而这些稳定表达情况在基于RNA的基因疗法上很难维持。



一项新的研究表明,通过引入RNA环可使现有基于RNA的基因治疗可能变得更加易于研究人员和临床医生控制。根据这项来自麻省理工学院的研究,编码治疗性蛋白质的RNA可以与编码RNA结合蛋白的RNA转录物一同转入靶细胞内,进而通过这些重新设计的RNA结合蛋白来调控小分子药物的机体表达剂量。



这项研究的领导者Tasuku Kitada教授表示,“他们重新设计了小分子反应性RNA结合蛋白,用以控制RNA编码遗传环路中蛋白质的表达。他们目前已经证明,利用他们这项全新的RNA编辑环可以有效控制靶蛋白的表达持续时间以及表达水平”。

简单点说,研究人员所设计的结合蛋白含有调控靶向蛋白表达的“ON and OFF”开关。通过这些开关可以十分方便的对蛋白表达进行控制。此外,ON和OFF开关的组合可以产生双输出开关,这样可使能够对两种基因的表达进行选择。这种开关可以让医生更准确地为个体患者提供量身定制的治疗方案。



Jacob Becraft教授表示:“由于复制的动态特性,研究人员可以通过RNA环来调整不同蛋白质在不同时间的表达,所有这些蛋白的序列均来自同一的RNA链。从以往基因疗法来看,目前的基因疗法遇到了安全性问题,但随着合成生物学的新进展,他们可以创造全新的“智能疗法”,进而更有效地使导入基因与患者自身细胞反应,最终提高就基因疗法的疗效和安全性”。



研究人员计划此新型RNA疗法来开发能够选择性地刺激免疫细胞攻击肿瘤的RNA环,从而可以靶向那些已经转移到目前药物难以进入部位的肿瘤细胞。例如,先前研究证明很难以mRNA直接靶向肿瘤细胞,因为这项技术可能导致肺组织出现炎症反应。但利用新型RNA环,研究人员可通过其遗传环激活可根除其他部位转移瘤的T细胞,最终杀灭所有肿瘤细胞。

研究人员表示,使用这些RNA环,医生可以根据患者的反应情况调整剂量。在患者的免疫系统过度刺激的情况下,这些RNA环路还提供了一种快速关闭治疗性蛋白质产生的方法,这可大大降低基因治疗并发症的出现。

在未来,研究人员希望开发更复杂的RNA环,使其既具有诊断功能又可以对疾病进行治疗。

原始出处:Wagner TE, Becraft JR, Bodner K, et al. Small-molecule-based regulation of RNA-delivered circuits in mammalian cells. Nat Chem Biol. 2018 Nov;14(11):1043-1050. 

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    2018-11-15 liye789132251
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    2019-08-04 sunylz
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    2018-10-21 kafei

    学习了谢谢

    0

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    2018-10-21 明月清辉

    谢谢分享,学习了

    0

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