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将CAG转换为CAA的碱基编辑策略可减少亨廷顿舞蹈病中的致病突变。

Base editing strategies to convert CAG to CAA diminish the disease-causing mutation in Huntington's disease.

作者信息

Choi Doo Eun, Shin Jun Wan, Zeng Sophia, Hong Eun Pyo, Jang Jae-Hyun, Loupe Jacob M, Wheeler Vanessa C, Stutzman Hannah E, Kleinstiver Ben, Lee Jong-Min

机构信息

Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States.

Department of Neurology, Harvard Medical School, Boston, United States.

出版信息

Elife. 2024 Jun 13;12:RP89782. doi: 10.7554/eLife.89782.

DOI:10.7554/eLife.89782
PMID:38869243
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11175616/
Abstract

An expanded CAG repeat in the huntingtin gene () causes Huntington's disease (HD). Since the length of uninterrupted CAG repeat, not polyglutamine, determines the age-at-onset in HD, base editing strategies to convert CAG to CAA are anticipated to delay onset by shortening the uninterrupted CAG repeat. Here, we developed base editing strategies to convert CAG in the repeat to CAA and determined their molecular outcomes and effects on relevant disease phenotypes. Base editing strategies employing combinations of cytosine base editors and guide RNAs (gRNAs) efficiently converted CAG to CAA at various sites in the CAG repeat without generating significant indels, off-target edits, or transcriptome alterations, demonstrating their feasibility and specificity. Candidate BE strategies converted CAG to CAA on both expanded and non-expanded CAG repeats without altering mRNA and protein levels. In addition, somatic CAG repeat expansion, which is the major disease driver in HD, was significantly decreased in the liver by a candidate BE strategy treatment in HD knock-in mice carrying canonical CAG repeats. Notably, CAG repeat expansion was abolished entirely in HD knock-in mice carrying CAA-interrupted repeats, supporting the therapeutic potential of CAG-to-CAA conversion strategies in HD and potentially other repeat expansion disorders.

摘要

亨廷顿基因（）中CAG重复序列的扩增会导致亨廷顿舞蹈病（HD）。由于HD的发病年龄由不间断CAG重复序列的长度而非聚谷氨酰胺决定，因此将CAG转换为CAA的碱基编辑策略有望通过缩短不间断CAG重复序列来延迟发病。在此，我们开发了将重复序列中的CAG转换为CAA的碱基编辑策略，并确定了它们的分子结果以及对相关疾病表型的影响。采用胞嘧啶碱基编辑器和引导RNA（gRNA）组合的碱基编辑策略能够在CAG重复序列的不同位点高效地将CAG转换为CAA，且不会产生显著的插入缺失、脱靶编辑或转录组改变，证明了其可行性和特异性。候选碱基编辑策略能在扩增和未扩增的CAG重复序列上都将CAG转换为CAA，且不改变mRNA和蛋白质水平。此外，在携带典型CAG重复序列的HD基因敲入小鼠中，通过候选碱基编辑策略治疗，肝脏中作为HD主要疾病驱动因素的体细胞CAG重复序列扩增显著减少。值得注意的是，在携带CAA中断重复序列的HD基因敲入小鼠中，CAG重复序列扩增完全消除，这支持了CAG到CAA转换策略在HD以及潜在的其他重复序列扩增疾病中的治疗潜力。

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