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Table 5 Cardiovascular disease and gene editing. Status: gene editing’s clinical utility in the cardiovascular realm

From: Gene editing in the context of an increasingly complex genome

Cardiovascular disease (CVD) consists of acute coronary syndrome (ACS), acute myocardial infarction (AMI), angina, arrhythmia, atherosclerosis, congestive heart failure (CHF), coronary artery disease (CAD), myocardial ischemia, etc. In the USA, per year, approximately 700,000 people suffer their first AMI and 500,000 experience a second or recurrent AMI, with 1.7 million being hospitalised annually due to ACS [242]. Clinical laboratories play a vital role in detecting and characterising risk of cardiovascular diseases and there is already a gambit of tests available for this purpose. For example, cardiac troponin is an important test for detecting myocardial injury, whilst B-type natriuretic peptide (BNP) and N-terminal portion of proBNP are used to detect CHF and risk for an acute event. Numerous other biomarkers are used to monitor various cardiovascular conditions.

However, not all biochemical tests are accurate. For example, it is known that half of AMIs occur in individuals with normal lipid panels [242]. The lipid panel (total, LDL, and HDL cholesterol, as well as triglycerides) —in addition to apolipoproteins (ApoA1 and ApoB), Lp(a), hsCRP, homocysteine, and Lp-pla2— are used to manage and monitor CHD. These tests can all be run using commercially-available reagents on various biochemical analysers, some of which may provide inaccurate results, possibly due to the complexity and stability of lipid molecules [243]. To improve the quality of results, alternative and more accurate methods have been developed to measure subclasses of HDL and LDL, such as: 1, β-quantification method [244], i.e., the reference method according to The U.S. National Cholesterol Education Program (NCEP); 2, gradient gel electrophoresis (GGE) [245, 246]; 3, vertical auto profile (VAP) [247]; 4, nuclear magnetic resonance spectroscopy (NMR) [245]; 5, ion mobility (IM) [248]; 6, high performance liquid chromatography (HPLC) [245].

Advances in the management of patients with cardiovascular disease through improved pharmacologic therapy have lessened impact; however, various limitations including patient compliance, side effects, and the need for repeat procedures keep patients in symptomatic status [249]. Gene and stem cell therapies in conjunction have shown promise in animal models of myocardial ischemia [249]. CRISPR/Cas9 gene editing of the loss-of-function proprotein convertase subtilisin/kexin type 9 (PCSK9) has also proven to reduce LDL cholesterol levels and protect against cardiovascular disease [250]. The major advantage of gene therapy is that, in a single administration, permanent benefits can be obtained, and with the advent of molecular research, further genes associated with lipoproteins and CVD risk have been discovered, e.g. APOA1, APOA5, APOE, CETP, GALNT2, LIPC, LPL, and MLXIPL [251], which may prove future targets of gene therapies.

Current gene therapy clinical trials have proven short-term safety; however, long term surveillance over a period of decades is still under investigation. Also, the cost-effectiveness of gene therapy has to be considered due to the laborious nature of the procedures. Current pharmacological approaches may still be more favourable in terms of cost benefit ratio [249], albeit in terms of cardiovascular disease treatment.