通过转换为类似miRNA的RNAi机制实现亨廷顿蛋白表达的等位基因选择性抑制。
Allele-selective inhibition of huntingtin expression by switching to an miRNA-like RNAi mechanism.
作者信息
Hu Jiaxin, Liu Jing, Corey David R
机构信息
The Departments of Pharmacology and Biochemistry, UT Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390-9041, USA.
出版信息
Chem Biol. 2010 Nov 24;17(11):1183-8. doi: 10.1016/j.chembiol.2010.10.013.
Abstract
Inhibiting expression of huntingtin (HTT) protein is a promising strategy for treating Huntington's disease (HD), but indiscriminant inhibition of both wild-type and mutant alleles may lead to toxicity. An ideal silencing agent would block expression of mutant HTT while leaving expression of wild-type HTT intact. We observe that fully complementary duplex RNAs targeting the expanded CAG repeat within HTT mRNA block expression of both alleles. Switching the RNAi mechanism toward that used by miRNAs by introducing one or more mismatched bases into these duplex RNAs leads to potent (<10 nM) and highly selective (>30-fold relative to wild-type HTT) inhibition of mutant HTT expression in patient-derived cells. Potent, allele selective inhibition of HTT by mismatched RNAs provides a new option for developing HD therapeutics.
摘要
抑制亨廷顿蛋白（HTT）的表达是治疗亨廷顿舞蹈症（HD）的一种有前景的策略，但不加区分地抑制野生型和突变型等位基因可能会导致毒性。理想的沉默剂应能阻断突变型HTT的表达，同时使野生型HTT的表达保持完整。我们观察到，靶向HTT mRNA中扩展的CAG重复序列的完全互补双链RNA会阻断两个等位基因的表达。通过在这些双链RNA中引入一个或多个错配碱基，将RNA干扰机制转变为微小RNA（miRNA）所使用的机制，可在患者来源的细胞中强效（<10 nM）且高度选择性地（相对于野生型HTT>30倍）抑制突变型HTT的表达。错配RNA对HTT的强效、等位基因选择性抑制为开发HD治疗药物提供了新的选择。
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