Lipid Nanoparticles Delivery of CRISPR/Cas9 Targeting PCSK9 and ANGTPL3 as New Therapeutic Gene Editing Modalities for Potential Long-Lasting Treatment Of Dyslipidemia

Abstract

Dyslipidemia is the main risk factor for atherosclerosis leading to cardiovascular disease, one of the important health problems in the Asia Pacific region. Several dyslipidemia treatment modalities such as statins and monoclonal antibodies were considered less effective both from the aspect of cost or toxic side effect. The aim of this study is to describe the potential of lipid nanoparticle-mediated efficient delivery of clustered regularly interspaced short palindromic repeat (CRISPR) associated protein 9 (CRISPR/Cas9) targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) and angiopoietin-like protein 3 (ANGPTL3) as new therapeutic genome editing modalities for potential long-lasting treatment of dyslipidemia. The method used in this study is to explore the literature in the form of systematic reviews, meta-analysis, and randomized control trials (RCTs) through several search engines such as Sciencedirect, Pubmed, and Google Schoolar in the last 10 years. The outcome of this study is to review the effectiveness of PCSK9 and ANGPTL3 inhibition in lowering cholesterol levels making both genes as a major therapeutic target for the treatment of dyslipidemia. Currently, an efficient way to permanently inhibit both genes has been developed using CRISPR-Cas9 genome editing delivered by lipid nanoparticles (LNPs), the most effective non-viral delivery modalities that work specifically on the liver. A single administration of LNPs-CRISPR/Cas9 in mice produced undetectable PCSK9 serum levels more than 80% and a drop of total cholesterol by 35%-40%. Meanwhile, CRISPR/Cas9 targeting ANGPTL3 resulted in a greater decrease in triglycerides on 7 day post-treatment. As a conclusion, genome editing therapy based on CRISPR/Cas9 lipid nanoparticles targeting PCSK9 and ANGPTL3 is promising for the treatment of dyslipidemia.