小柯机器人

美国麻省理工学院和哈佛大学Broad研究所David R. Liu小组报道使用双-腺相关病毒（AAV）对小鼠大脑、肝脏和心脏进行高效编辑的先导编辑（PE）。相关论文于2023年5月4日发表在《自然-生物技术》杂志上。

研究人员揭示了限制体内腺相关病毒介导先导编辑的瓶颈，构建了PE表达增加、先导编辑指导RNA稳定性和DNA修复调节的AAV-PE载体。由此产生的双AAV系统v1em和v3em PE-AAV能够在小鼠大脑（皮层效率可达42）、肝脏（可达46）和心脏（可达11）中进行治疗相关的先导编辑。

研究人员利用该系统在阿尔茨海默病的星形胶质细胞和冠状动脉疾病患者的肝细胞中引入了假定的保护性突变。使用v3em PE-AAV进行体内先导编辑未产生可检测到的脱靶效应或肝酶或组织学显著变化。优化的PE-AAV系统产生了迄今为止报道的最高未富集水平的体内先导编辑，促进了对遗传疾病的研究和潜在治疗。

据悉，利用先导编辑对遗传性疾病进行研究和治疗需要将先导编辑器递送到体内的有效方法。

附：英文原文

Title: Efficient prime editing in mouse brain, liver and heart with dual AAVs

Author: Davis, Jessie R., Banskota, Samagya, Levy, Jonathan M., Newby, Gregory A., Wang, Xiao, Anzalone, Andrew V., Nelson, Andrew T., Chen, Peter J., Hennes, Andrew D., An, Meirui, Roh, Heejin, Randolph, Peyton B., Musunuru, Kiran, Liu, David R.

Issue&Volume: 2023-05-04

Abstract: Realizing the promise of prime editing for the study and treatment of genetic disorders requires efficient methods for delivering prime editors (PEs) in vivo. Here we describe the identification of bottlenecks limiting adeno-associated virus (AAV)-mediated prime editing in vivo and the development of AAV-PE vectors with increased PE expression, prime editing guide RNA stability and modulation of DNA repair. The resulting dual-AAV systems, v1em and v3em PE-AAV, enable therapeutically relevant prime editing in mouse brain (up to 42% efficiency in cortex), liver (up to 46%) and heart (up to 11%). We apply these systems to install putative protective mutations in vivo for Alzheimer’s disease in astrocytes and for coronary artery disease in hepatocytes. In vivo prime editing with v3em PE-AAV caused no detectable off-target effects or significant changes in liver enzymes or histology. Optimized PE-AAV systems support the highest unenriched levels of in vivo prime editing reported to date, facilitating the study and potential treatment of diseases with a genetic component.

DOI: 10.1038/s41587-023-01758-z

Source: https://www.nature.com/articles/s41587-023-01758-z

Nature Biotechnology：《自然—生物技术》，创刊于1996年。隶属于施普林格·自然出版集团，最新IF：68.164
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