Zuo, YuanbojiaoZhang, ChenZhou, YuanLi, HaiwenXiao, WeidongHerzog, Roland W.Xu, JieZhang, JifengChen, Y. EugeneHan, Renzhi2024-01-172024-01-172023-06-15Zuo Y, Zhang C, Zhou Y, et al. Liver-specific in vivo base editing of Angptl3 via AAV delivery efficiently lowers blood lipid levels in mice. Cell Biosci. 2023;13(1):109. Published 2023 Jun 15. doi:10.1186/s13578-023-01036-0https://hdl.handle.net/1805/38032Background: 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. Results: 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. Conclusions: These results highlight the promise of liver-targeted Angptl3 base editing for blood lipid control.en-USAttribution 4.0 InternationalANGPTL3CholesterolBase editingBase editorCardiovascular diseaseCVDTriglycerideArticle