基于基因编辑的心脏靶向纳米复合物CTP-PEI-PEG-Cas9/gRNA的研究

CRISPER/Cas9是近年来兴起的基因编辑技术，有望被用于基因突变相关的心肌病的治疗。该技术目前因缺乏安全有效的心脏靶向递送载体限制了其在心肌病领域中的研究和应用。本课题组前期研究构建出心肌靶向聚合物CTP-PEI-PEG，并证实该聚合物体内静脉注射后主要聚集于心脏，并可有效将目标基因（CAG-Cre质粒）靶向递送到心脏。本课题拟用CTP-PEI-PEG作为CRISPER/Cas9的递送载体，构建CTP-PEI-PEG-Cas9/gRNA复合物，并验证该复合物经静脉注射后能否有效靶向到心肌细胞内对目标基因进行剪切，将CRISPER/Cas9的基因编辑精准定位到心脏，最大限度降低对非靶器官的基因编辑。为今后CRISPER/Cas9技术用于心肌病的靶向基因治疗提供理论基础。

CRISPER/Cas9 is a new genome editing tool which has raised expectations for correcting mutation gene related to cardiomyopathies. However, it has remained difficult to use CRISPER/Cas9 to edit the gene due to delivery challenges of the CRISPER/Cas9 components. Our group made the cardiac targeting nanoparticle CTP-PEI-PEG, we found that after injecting in vivo, most nanoparticle is accumulated in the heart, only little uptake by the other organ, CTP-PEI-PEG can also targetedly delivery the gene into the heart. In this study, we plan to use this nanoparticle to delivery CRISPER/Cas9, make CTP-PEI-PEG-Cas9/gRNA which enables robust genomic editing exclusively in cardiomyocytes, with minimum off-target effect. Our study provides a means of specific and efficient editing gene of interest in heart.