Nat Med:特异性等位基因编辑能够预防耳聋

2019-07-23 AlexYang MedSci原创

由于大多数人类的变异均为单核苷酸替换,最近,有研究人员探索了基因编辑策略来干扰显性变异效果,并选择性的避开对野生型等位基因的影响。然而,当前常用的内切酶比如酿脓链球菌Cas9(SpCas9)能够接受向导RNA(gRNA)和靶标RNA之间多达7个核苷酸的差异,因而很难做到对单个核苷酸的区分。更多的是,前间区序列邻近基序(PAM)在一些Cas9酶中也能够接受与靶DNA的错配情况。最近,有研究人员为了克

由于大多数人类的变异均为单核苷酸替换,最近,有研究人员探索了基因编辑策略来干扰显性变异效果,并选择性的避开对野生型等位基因的影响。然而,当前常用的内切酶比如酿脓链球菌Cas9(SpCas9)能够接受向导RNA(gRNA)和靶标RNA之间多达7个核苷酸的差异,因而很难做到对单个核苷酸的区分。更多的是,前间区序列邻近基序(PAM)在一些Cas9酶中也能够接受与靶DNA的错配情况。

最近,有研究人员为了克服这些限制,他们筛选了14个Cas9/gRNA组合,从而实现对引起显性进行性听力损失的单个核苷酸替换的特异有效编辑。作为DFNA36的一个模型,研究人员利用一个在Tmc1中携带点突变的小鼠模型来进行相关研究。在内耳毛细胞中,Tmc1编码一个机械感应通道的成孔亚基,且对听力的形成是需要的。研究人员鉴定到了金黄色酿脓葡萄球菌Cas9(SaCas9-KKH)的一个PAM变体,该变体在小鼠和DFNA36人类细胞系中能够选择性的和有效的编辑突变等位基因,而对野生型等位基因没有作用。

最后,研究人员指出,腺相关病毒(AAV)介导的SaCas9-KKH传输能够在注射后预防耳聋长达1年。对现有的ClinVar数据分析表明,大约21%的人类显性变异可以通过相似的方法来进行靶向编辑。

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    2020-03-03 liye789132251
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