Abstract Body: Hyperlipidemia has emerged as the prominent etiological factors for the morbidity and mortality associated with cardiovascular disease. Targeting angiopoietin-like 3 (ANGPTL3), proprotein convertase subtilisin/kexin type 9 (PCSK9) and asialoglycoprotein receptor 1 (ASGR1) are considered as an alternative therapeutic approach for the regulation of blood lipid level and thereby reducing the hyperlipidemia-induced cardiovascular diseases. In this study, we aimed to use CRISPR/Cas9 base editing system to disrupt the expression of genes, ANGPTL3, PCSK9 and ASGR1 for the control of hyperlipidemia. Here, we tested the various combination of base editor targeting either the acceptor splice site or donor splice site to knockdown the expression of ANGPTL3, PCSK9 and ASGR1. In vivo injection of AAV8 vector targeting the exon 4 splice donor of ASGR1, exon 1 splice donor site of PCSK9 and exon 6 splice donor site of ANGPTL3 exhibited reduced protein expression of Asgr1, Pcsk9 and Angptl3 level. Similarly, the serum lipids levels were also found to be reduced in the mice injected with AAV8 and was maintained in AAV8 injected mice up to 12 weeks post high-fat diet. Later, in this study, we aimed to explore the combined base editing approach for the control of hyperlipidemia.