Liver-specific in vivo base editing of Angptl3 via AAV delivery efficiently lowers blood lipid levels in mice.
Liver-specific in vivo base editing of Angptl3 via AAV delivery efficiently lowers blood lipid levels in mice.
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DOI：
10.1186/s13578-023-01036-0
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发表时间：
2023-06-15
影响因子：
7.5
通讯作者：
Han, Renzhi
中科院分区：
文献类型：
--
作者：
Zuo, Yuanbojiao;Zhang, Chen;Zhou, Yuan;Li, Haiwen;Xiao, Weidong;Herzog, Roland W.;Xu, Jie;Zhang, Jifeng;Chen, Y. Eugene;Han, Renzhi
基因编辑已经成为许多遗传性和非遗传性疾病的令人兴奋的治疗开发平台。以血管生成素相关蛋白3(Angptl3)等脂质调节基因为靶点进行基因编辑，为降低与高胆固醇血症相关的心血管疾病风险带来了希望。在这项研究中，我们开发了一种由双腺相关病毒(AAV)传递的肝细胞特异性碱基编辑治疗方法，以使肝细胞特异性靶向Angptl3降低血脂水平。AAV9介导的胞嘧啶碱基编辑基因AncBE4max靶向于小鼠Angpt1 3，在小鼠肝组织中安装了提前终止密码子，平均效率为63.3 ± 2.3%。在接种AAV后的2-4周内，观察到循环中的Angptl3蛋白几乎完全被敲除。此外，治疗4周后，血清甘油三酯(TG)和总胆固醇(TC)水平分别下降了约58%和61%。这些结果突出了以肝脏为靶点的Angptl3碱基编辑用于血脂控制的前景。网上版载有补充材料，可在10.1186/s13578-023-01036-0查阅。
Gene editing has emerged as an exciting therapeutic development platform for numerous genetic and nongenetic diseases. Targeting lipid-modulating genes such as angiopoietin-related protein 3 (ANGPTL3) with gene editing offers hope for a permanent solution to lower cardiovascular disease risks associated with hypercholesterolemia. In this study, we developed a hepatocyte-specific base editing therapeutic approach delivered by dual adeno-associated virus (AAV) to enable hepatocyte-specific targeting of Angptl3 to lower blood lipid levels. Systemic AAV9-mediated delivery of AncBE4max, a cytosine base editor (CBE), targeting mouse Angptl3 resulted in the installation of a premature stop codon in Angptl3 with an average efficiency of 63.3 ± 2.3% in the bulk liver tissue. A near-complete knockout of the ANGPTL3 protein in the circulation were observed within 2–4 weeks following AAV administration. Furthermore, the serum levels of triglyceride (TG) and total cholesterol (TC) were decreased by approximately 58% and 61%, respectively, at 4 weeks after treatment. These results highlight the promise of liver-targeted Angptl3 base editing for blood lipid control. The online version contains supplementary material available at 10.1186/s13578-023-01036-0.
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