The Future of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 Gene Therapy in Cardiomyopathies: A Review of Its Therapeutic Potential and Emerging Applications

Figures

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  Figure 1. Utilization of CRISPR-Cas9 for genetic correction of hypertrophic cardiomyopathy (HCM) CRISPR: clustered regularly interspaced short palindromic repeats; Cas9: CRISPR-associated protein 9 The figure illustrates the process of correcting a specific genetic mutation associated with HCM, which is characterized by the abnormal thickening of the heart muscle, particularly in the left ventricle and septum. The MYH7 gene mutation c.1208G>A (p.Arg403Gln) leads to the substitution of arginine (Arg) with glutamine (Gln) in the β-myosin heavy chain protein, resulting in hypertrophy of cardiomyocytes. The CRISPR-Cas9 system, delivered via AAV9 vectors, targets and corrects this mutation by converting the mutated G back to A, thereby restoring normal gene function. Postediting outcomes include reduced myocyte hypertrophy, decreased cardiac fibrosis, and restoring normal cardiac structure and function, leading to a healthier heart. Image created by the authors

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  Figure 2. Application of CRISPR-Cas9 gene editing in the study and treatment of DCM DCM: dilated cardiomyopathy; CRISPR: clustered regularly interspaced short palindromic repeats; Cas9: CRISPR-associated protein 9 The figure illustrates the use of CRISPR-Cas9 technology to target and edit mutations in crucial genes associated with DCM, such as TTN, LMNA, and SCN5A. The process includes the delivery of the CRISPR-Cas9 machinery via AAV9-based vectors, which enables the correction of genetic defects, resulting in restored heart muscle function, improved electrical conduction, and reduced ventricular dilation. This approach demonstrates the potential of gene editing in addressing the genetic causes of DCM and improving cardiac health. Image created by the authors

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  Figure 3. Schematic representation of ARVC highlighting the genetic basis and potential therapeutic intervention using CRISPR-Cas9 AVRC: arrhythmogenic right ventricular cardiomyopathy; PKP2: plakophilin 2; DSP: desmoplakin; DSG2: desmoglein-2; DSC2: desmoscollin-2; JUP: junctional-plakophilin; CRISPR: clustered regularly interspaced short palindromic repeats; Cas9: CRISPR-associated protein 9 ARVC predominantly affects the right ventricle, leading to irregular heart rhythms and an increased risk of sudden cardiac death. The condition is associated with mutations in desmosomal genes (PKP2, DSP, DSG2, DSC2, and JUP), which compromise the structural integrity of cardiomyocytes. The figure illustrates the delivery of CRISPR-Cas9 via an AAV9 vector to target and correct these mutations. Outcomes of successful gene editing include enhanced cell-cell adhesion, improved electrical conductivity, normalization of desmosomal protein expression, repaired desmosomal integrity, increased resistance to stress-induced separation, restoration of cardiac function, and reduced arrhythmias. Image created by the authors