RNA反式剪接治疗杜氏肌营养不良症
RNA trans-splicing treatment for Duchenne muscular dystrophy
bioRxiv · 2026 年 9 月 16 日 · Ryan H Hsu, Claire E Williams, Geraldine Maier 等 11 人
杜氏肌营养不良症（DMD）由抗肌萎缩蛋白（dystrophin）基因突变引起，肌肉逐渐退化并最终导致心力衰竭，目前AAV基因治疗受载体容量限制难以递送大基因。研究者开发了多载体RNA末端连接（REJ）系统，把大基因拆成多段分别装入多个AAV，利用细胞自身的剪接体（负责拼接RNA的机器）把RNA片段精确重组成完整的大蛋白。小鼠体内实验显示，表达碱基编辑器Abe8e、微型抗肌萎缩蛋白Dp253或天然全长Dp427的REJ载体均能防止肌肉退化；对超过12万条肌纤维的机器学习病理分析显示核浸润减少、中心核化和肥大改善，并有功能、转录组和行为学证据支持。这意味着REJ可能成为临床可行的DMD AAV治疗策略，同时避免细菌蛋白或DNA重组酶带来的抗原性。该研究尚未经同行评审。
为什么推荐给您：新型多载体RNA重组平台首次实现全长抗肌萎缩蛋白体内递送，属重要新模态的动物阳性结果。
不需要生物学背景，多打比方
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摘要Abstract
Duchenne muscular dystrophy (DMD) is a fatal disorder caused by dystrophin mutations, leading to progressive muscle degeneration and cardiac failure. Although AAV-based DMD therapies with innovative designs to overcome the cargo limits of the virus are effective in animal models, these current systems may face clinical translation challenges related to efficiency, off-target effects, and immunogenicity. We developed a multi-vector RNA End Joining (REJ) system to split large genes into multiple co-delivered AAVs that engage the cell's intrinsic spliceosome to precisely reassemble RNA segments that encode very large scar-free proteins. We show the system is efficient and has negligible off-target interactions. In vivo , REJ vectors expressing the adenine base editor Abe8e, mini-dystrophin Dp253, or native full-length dystrophin Dp427 each prevented muscle degeneration. Machine-learning histopathology of more than 120,000 myofibers revealed robust reductions in nuclear infiltration, improved centronucleation, and normalized hypertrophy, supported by functional, transcriptomic, and behavioral analyses. These findings establish REJ as a clinically viable AAV-based strategy for DMD that enables expression of large therapeutic proteins while avoiding potentially antigenic bacterial protein- or DNA-recombinases.