The Future of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 Gene Therapy in Cardiomyopathies: A Review of Its Therapeutic Potential and Emerging Applications.
Division
West Florida
Hospital
Blake Medical Center
Document Type
Manuscript
Publication Date
2-20-2025
Keywords
arrhythmogenic right ventricular cardiomyopathy (arvc/d), cardiomyopathy, CRISPR, CRISPR Cas, CRISPR-Cas9-mediated gene editing, CRISPR/Cas9 gene editing, dilated cardiomyopathy, hcm, hypertrophy cardiomyopathy
Disciplines
Cardiovascular Diseases | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Internal Medicine | Medicine and Health Sciences
Abstract
Cardiomyopathies, among the leading causes of heart failure and sudden cardiac death, are often driven by genetic mutations affecting the heart's structural proteins. Despite significant advancements in understanding the genetic basis of hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC), effective long-term therapies remain limited. The advent of clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) gene editing offers a promising therapeutic strategy to address these genetic disorders at their root. CRISPR-Cas9 enables precise modification of pathogenic variants (PVs) in genes encoding sarcomeric and desmosomal proteins, which are frequently implicated in cardiomyopathies. By inducing site-specific double-stranded breaks in DNA, followed by repair through nonhomologous end joining (NHEJ) or homology-directed repair (HDR), this system allows for targeted correction of mutations. In preclinical models, CRISPR-Cas9 has shown promise in correcting HCM-associated mutations in β-myosin heavy chain 7 (MYH7), preventing disease phenotypes such as ventricular hypertrophy and myocardial fibrosis. Similarly, gene editing has successfully rectified DCM-linked mutations in Titin (TTN) and LMNA, resulting in improved heart function and reduced pathological remodeling. For ARVC, CRISPR-Cas9 has demonstrated the ability to repair mutations in desmosomal genes such as plakophilin 2 (PKP2), thereby restoring normal cardiac function and cellular adhesion. Despite these successes, challenges remain, including mosaicism, delivery efficiency, and off-target effects. Nevertheless, CRISPR-Cas9 represents a transformative approach to treating genetic cardiomyopathies, potentially offering long-lasting cures by directly addressing their underlying genetic causes.
Publisher or Conference
Cureus
Recommended Citation
Moradi A, Khoshniyat S, Nzeako T, et al. The Future of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 Gene Therapy in Cardiomyopathies: A Review of Its Therapeutic Potential and Emerging Applications. Cureus. 2025;17(2):e79372. doi:10.7759/cureus.79372
