CRISPR/Cas9-Mediated Knockout of APOC3 Stabilizes Plasma Lipids and Inhibits Atherosclerosis in Rabbits

Abstract

Background: High levels of apolipoprotein C3 (APOC3) can lead to hypertriglyceridemia, which increases the risk of cardiovascular disease. We aim to create APOC3 knockout (KO) rabbits and explore the effects of APOC3 deletion on the occurrence and development of atherosclerosis.Methods: A sgRNA anchored to exon 2 of APOC3 was designed to edit embryos using the CRISPR/Cas9 system. The founder rabbits were sequenced, and their lipid profile, inflammatory cytokines and atherosclerotic plaques were analyzed.Results: When given a normal chow (NC) diet, all APOC3 KO rabbits had low plasma TG level, which was two times lower than that of the matched age control group. Additionally, their plasma lipoprotein lipase (LPL) increased. When fed a high-fat diet (HFD), it was observed that APOC3 deficiency was more conducive to the maintenance of plasma TG, total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels in rabbits, the inhibition of inflammatory response and the protection of atherosclerosis in rabbits.Conclusion: APOC3 KO rabbit models can be obtained with the CRISPR/Cas9 system to combat the formation of HFD-induced atherosclerosis, indicating a novel therapeutic target to treat atherosclerosis.

Applying the CRISPR/Cas9 for Treating Human and Animal Diseases – Comprehensive Review

“…According to many previous works (Kizilay Mancini et al, 2021), it was established that HCL is an inherited ailment caused by the mutation of some genes and the vastly prevalent kind of genetics recognized as HCH (hypercholesterolemia). The genomic mutations are well documented involving this disease (ART), such as the PCSK9, or LDL receptor (LDLR), and apolipoprotein B (APOB), were in accounting for 1%, 90%, and 5% of HCL cases, respectively (Kizilay Mancini et al, 2021;Zha et al, 2021). Cho et al (2020) reported an improvement in the survivalist of transplanted rats using CRISPR/Cas9 for targeting the LEF1 gene (lymphoid enhancer binding factor 1).…”

“…They found that the CRISPR/Cas9 tactic can ameliorate the APOC3 expression and reduce ART plaque formation. The anti-atherosclerotic properties of APOC3 suppression therapy exhibited a robust gene editing strategy and could provide a considerable fact for developing new therapy and further clinical uses (Zha et al, 2021). Still, there are lack trials of the applying of CRISPR/Cas9 tool for treating the HCL or ART diseases in humans or animals (as models).…”