通过环状arRNA引导的外显子跳跃在猴子和人类中长期逆转杜氏肌营养不良症
通过环状arRNA引导的外显子跳跃在猴子和人类中长期逆转杜氏肌营养不良症
作者： 小柯机器人 发布时间：2026/6/11 17:08:48
本期文章：《细胞》：Online/在线发表
近日，北京大学魏文胜团队通过环状arRNA引导的外显子跳跃在猴子和人类中长期逆转杜氏肌营养不良症。相关论文于2026年6月10日发表在《细胞》杂志上。
该研究组利用内源性腺苷脱氨酶作用于RNA （ADAR）进行RNA可编程编辑（LEAPER） 2.0，这是一个RNA编辑平台，通过利用内源性ADAR通过环状ADAR招募RNA （circ-arRNAs）实现外显子跳跃。通过接合关键剪接元件，circ-arRNAs绕过帧外DMD突变，通过ADAR依赖性和ADAR非依赖性机制恢复肌营养不良蛋白的表达。
在携带热点突变的DMD非人灵长类动物（NHPs）中，单次给药可以实现持久的肌营养不良蛋白恢复和至少1.5年的运动改善，而不会引起抗肌营养不良蛋白免疫反应。在一项首次人体研究中，单剂量腺相关病毒（AAV）递送的circ-arRNA在三名患者中产生了安全的、剂量依赖性的外显子跳跃，并伴有运动和心肺功能的可测量增益。总之，在DMD NHP模型、患者源性心肌细胞和治疗患者中一致的肌营养不良蛋白恢复突出了circ-arRNA介导的外显子跳变作为DMD治疗策略的翻译潜力。
据了解，杜氏细胞营养不良症（DMD）是一种由DMD基因突变引起的致命神经细胞疾病，可导致进行性细胞变性、活动能力丧失和过早死亡。
附：英文原文
Title: Long-term reversal of Duchenne muscular dystrophy via circular arRNA-guided exon skipping in monkeys and humans
Author: Wenting Guo, Huixian Tang, Zongyi Yi, Ting Zhang, Pengfei Yuan, Cuijin Wang, Shuaiwei Ren, Xiwen Chang, Jiwu Ren, Wei Tang, Wenjie Sun, Jie Liu, Ying Yu, Zhiwei Lu, Hongyan Shen, Zexuan Yi, Yanxia Zhao, Gangbin Tang, Junyuan Han, Wenzhi Zhang, Haoyue Liu, Xueqing Sun, Yongjian Zhang, Cui Zhang, Yuming Wu, Ling Yang, Feng Han, Yichao Xu, Liang Qu, Xinyan Sun, Jiwen Wang, Weizhi Ji, Yongchang Chen, Wensheng Wei
Issue&Volume: 2026-06-10
Abstract: Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disorder caused by mutations in the DMD gene, leading to progressive muscle degeneration, loss of mobility, and premature death. Here, we applied leverage endogenous adenosine deaminase acting on RNA (ADAR) for programmable editing of RNA (LEAPER) 2.0, an RNA editing platform, to achieve exon skipping by harnessing endogenous ADAR through circular ADAR-recruiting RNAs (circ-arRNAs). By engaging key splicing elements, circ-arRNAs bypass out-of-frame DMD mutations and restore dystrophin expression through ADAR-dependent and ADAR-independent mechanisms. In DMD nonhuman primates (NHPs) carrying hotspot mutations, a single administration achieved durable dystrophin restoration and sustained motor improvement for at least 1.5 years without eliciting anti-dystrophin immune responses. In a first-in-human study, a single dose of adeno-associated virus (AAV)-delivered circ-arRNA produced safe, dose-dependent exon skipping in three patients, accompanied by measurable gains in motor and cardiopulmonary function. Together, consistent dystrophin restoration across DMD NHP models, patient-derived cardiomyocytes, and treated patients highlights the translational potential of circ-arRNA-mediated exon skipping as a therapeutic strategy for DMD.
DOI: 10.1016/j.cell.2026.05.030
Source: https://www.cell.com/cell/abstract/S0092-8674(26)00589-1