Zuo Yuanbojiao, Zhang Chen, Zhou Yuan, Li Haiwen, Xiao Weidong, Herzog Roland W, Xu Jie, Zhang Jifeng, Chen Y Eugene, Han Renzhi
Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
Department of Surgery, The Ohio State University, Columbus, OH, 43210, USA.
Cell Biosci. 2023 Jun 15;13(1):109. doi: 10.1186/s13578-023-01036-0.
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.
基因编辑已成为一种用于多种遗传和非遗传疾病的令人兴奋的治疗开发平台。通过基因编辑靶向血管生成素相关蛋白3（ANGPTL3）等脂质调节基因，为永久性降低与高胆固醇血症相关的心血管疾病风险提供了希望。
在本研究中，我们开发了一种由双腺相关病毒（AAV）递送的肝细胞特异性碱基编辑治疗方法，以实现对Angptl3的肝细胞特异性靶向，从而降低血脂水平。全身性AAV9介导的靶向小鼠Angptl3的胞嘧啶碱基编辑器（CBE）AncBE4max的递送，导致在Angptl3中安装了一个提前终止密码子，在肝脏组织整体中的平均效率为63.3±2.3%。在给予AAV后的2至4周内，观察到循环中ANGPTL3蛋白几乎完全敲除。此外，治疗后4周时，甘油三酯（TG）和总胆固醇（TC）的血清水平分别降低了约58%和61%。
这些结果突出了肝脏靶向性Angptl3碱基编辑在血脂控制方面的前景。
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