The success of base editors for the study and treatment of genetic diseases depends on the ability to deliver them in vivo to the relevant cell types. Delivery via adeno-associated viruses (AAVs) is limited by AAV packaging capacity, which precludes the use of full-length base editors. Here, we report the application of dual AAVs for the delivery of split cytosine and adenine base editors that are then reconstituted by trans-splicing inteins. Optimized dual AAVs enable in vivo base editing at therapeutically relevant efficiencies and dosages in the mouse brain (up to 59% of unsorted cortical tissue), liver (38%), retina (38%), heart (20%) and skeletal muscle (9%). We also show that base editing corrects, in mouse brain tissue, a mutation that causes Niemann-Pick disease type C (a neurodegenerative ataxia), slowing down neurodegeneration and increasing lifespan. The optimized delivery vectors should facilitate the efficient introduction of targeted point mutations into multiple tissues of therapeutic interest.

中文翻译：

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通过腺相关病毒对小鼠的大脑、肝脏、视网膜、心脏和骨骼肌进行胞嘧啶和腺嘌呤碱基编辑。

用于研究和治疗遗传疾病的碱基编辑器的成功取决于将它们在体内传递到相关细胞类型的能力。通过腺相关病毒 (AAV) 的传递受到 AAV 包装容量的限制，这排除了使用全长碱基编辑器。在这里，我们报告了双 AAV 在传递分裂的胞嘧啶和腺嘌呤碱基编辑器中的应用，然后通过反式剪接内含肽进行重组。优化的双 AAV 能够在小鼠大脑（高达 59% 的未分类皮质组织）、肝脏（38%）、视网膜（38%）、心脏（20%）和骨骼肌中以治疗相关的效率和剂量进行体内碱基编辑（ 9%）。我们还表明，碱基编辑可以纠正小鼠脑组织中导致 Niemann-Pick 病 C 型（一种神经退行性共济失调）的突变，减缓神经退行性变，延长寿命。优化的递送载体应有助于将靶向点突变有效地引入多个具有治疗意义的组织中。