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用高精度RNA核酶 (CRISPR-Cas13d) 抑制基因特异性MHC变体防止高性心肌病

Ping Yang¹, Yingmei Lou¹, Zilong Geng¹

¹Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Engineering Research Center of Techniques and Instruments for Diagnosis and Treatment of Congenital Heart Disease, Institute for Developmental and Regenerative Medicine, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China (P.Y., Y. Lou, Z. Geng, Z. Guo, S.W., Y. Li, K.S., S.Z., J.X., A.F.C., L.D., K.S., B.Z.).

|May 16, 2024

概括

一种新型的CRISPR-Cas13变异精确地准并纠正导致心肌缩的MYH7基因突变. 这种基因治疗方法通过预防小鼠模型中的心脏缩来治疗遗传性心脏病.

科学领域:

心血管遗传学
分子生物学
基因治疗

背景情况:

家族性缩性心肌病是一种严重的遗传性疾病,具有严重的临床后果.
瘤基因中的异构单核酸变体 (SNV),特别是MYH7,是HCM的主要原因.
基因编辑工具CRISPR-Cas13具有遗传性疾病的潜力, 但其在心肌病中的应用尚未被探索.

研究的目的:

开发一种高度精确的CRISPR-Cas13变体,用于向MYH7SNV的高缩性心肌病.
在体外和体内评估工程CRISPR-Cas13变异的疗效和特异性.
探索基于CRISPR-Cas13的基因治疗对遗传性心脏病的治疗潜力.

主要方法:

开发了一种敏感的报告系统,用于选Cas13d变种的突变性活动.
设计了一个高精度的Cas13d变体 (hpCas13d),具有MYH7变体RNA的特定裂变.
在体外验证了hpCas13d的精度和低附带裂变;在HCM小鼠模型中使用AAV9输送到心肌细胞进行了测试.
进行了大规模的图书馆查,以评估hpCas13d能够解决45种人类MYH7致病性SNV.

主要成果:

野生型Cas13d未能与SNV区分异构MYH7等位基因.
改造的hpCas13d变体显示了最小的附带RNase活动,并解决了各种MYH7病理序列变异.
在两种不同的HCM小鼠模型中进行体内应用,抑制了改变的MYH7等位基因,并预防了心脏缩.

结论:

CRISPR-Cas核酶为精确治疗遗传性心肌病提供了显著的潜力.
这项研究确立了治疗遗传性心脏病的新策略.
高精度基因编辑为遗传性心肌病治疗提供了一个有前途的途径.

关键词:

心肌病,高性心肌病,过度缩,家族性治疗药物

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相关概念视频

CRISPR

CRISPR

Genome editing technologies allow scientists to modify an organism’s DNA via the addition, removal, or rearrangement of genetic material at specific genomic locations. These types of techniques could potentially be used to cure genetic disorders such as hemophilia and sickle cell anemia. One popular and widely used DNA-editing research tool that could lead to safe and effective cures for genetic disorders is the CRISPR-Cas9 system. CRISPR-Cas9 stands for Clustered Regularly Interspaced...