Abstract
Atherosclerosis represents one of the major causes of death globally. The high mortality rates and limitations of current therapeutic modalities have urged researchers to explore potential alternative therapies. The clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR/Cas9) system is commonly deployed for investigating the genetic aspects of Atherosclerosis. Besides, advances in CRISPR/Cas system has led to extensive options for researchers to study the pathogenesis of this disease. The recent discovery of Cas9 variants, such as dCas9, Cas9n, and xCas9 have been established for various applications, including single base editing, regulation of gene expression, live-cell imaging, epigenetic modification, and genome landscaping. Meanwhile, other Cas proteins, such as Cas12 and Cas13, are gaining popularity for their applications in nucleic acid detection and single-base DNA/RNA modifications. To date, many studies have utilized the CRISPR/Cas9 system to generate disease models of atherosclerosis and identify potential molecular targets that are associated with atherosclerosis. These studies provided proof-of-concept evidence which have established the feasibility of implementing the CRISPR/Cas system in correcting disease-causing alleles. The CRISPR/Cas system holds great potential to be developed as a targeted treatment for patients who are suffering from atherosclerosis. This review highlights the advances in CRISPR/Cas systems and their applications in establishing pathogenetic and therapeutic role of specific genes in atherosclerosis.
Highlights
Cardiovascular diseases (CVDs) refer to a group of disorders that affect the heart and blood vessels, including hypertension, coronary heart disease, heart failure, rheumatic heart disease, congenital heart disease and cardiomyopathies, cerebrovascular disease, and peripheral vascular disease [1]
Specific base editing was successfully achieved by using a base editor 3 (BE3), which comprises of a CRISPR/Cas9 that is fused to a cytosine deaminase domain, and the resulting gene-edited mice showed more than 50% reduction of plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) protein levels and approximately 30% reduction of cholesterol levels without detectable off-target mutagenesis [108]
This study has successfully demonstrated the cardio-protect effect of LEF1 gene and potential for combining the stem cell-based therapy with genome editing technique as a therapeutic strategy for treating cardiovascular diseases [58]
Summary
Cardiovascular diseases (CVDs) refer to a group of disorders that affect the heart and blood vessels, including hypertension, coronary heart disease, heart failure, rheumatic heart disease, congenital heart disease and cardiomyopathies, cerebrovascular disease, and peripheral vascular disease [1]. Numerous experimental studies have shown that correction of single gene defect can be achieved by the use of CRISPR/Cas technology in atherosclerosis models This genome editing tool provides compelling alternatives to current treatment options (statins and ezetimibe), which require multiple dosages during the course of the disease. Another strategy to evaluate off-target assessment in vivo, known as ‘verification of in vivo off-targets’ (VIVO), was developed and involves the identification of off-target sites using the CIRcularization for in vitro reporting of CLEavage effects by sequencing (CIRCLE-seq) method [81], followed by confirmation through the targeted amplicon sequencing approach [82] This strategy was shown to be robust and sensitive in detecting off-target mutations with minimal frequencies (0.13%) [82]
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