Clustered Regularly Interspaced Short Palindromic Repeats Genome Editing for Cardiovascular Disease: The Future Is Here.
Academic Article
Overview
abstract
Clustered regularly interspaced short palindromic repeats (CRISPR)-based genome editing has expanded from experimental biology to early clinical application, raising the possibility of durable therapies for cardiovascular disease. Because many cardiac conditions are monogenic, they provide clear targets for allele-specific correction or modulation. In hypertrophic cardiomyopathy, preclinical research has shown that base editing of pathogenic MYH7 and MYBPC3 mutations can restore sarcomere function; concurrently, RNA-targeting approaches selectively suppress mutant transcripts. Dilated cardiomyopathy is more heterogeneous: TTN truncations cause haploinsufficiency that can be offset by CRISPR activation, while RBM20 and LMNA mutations require precise correction or interference to restore splicing and nuclear stability. Genome editing is also being tested in familial hypercholesterolemia, where inactivation of PCSK9 using lipid nanoparticle-delivered base editors has now advanced to first-in-human trials, achieving sustained LDL-C lowering. Concurrently, efforts targeting ANGPTL3 and APOB highlight the prospect of multigene modulation of lipid metabolism. In arrhythmic syndromes, patient-derived cardiomyocytes edited at SCN5A and KCNQ1 genes have enabled high-fidelity disease models, while in vivo correction of RYR2 in catecholaminergic polymorphic ventricular tachycardia confirms the viability of editing an arrhythmia substrate. In cardiac regeneration, CRISPR activation of developmental transcription factors has enabled direct reprogramming of fibroblasts into cardiomyocyte-like cells within scar tissue. Even with these advances, delivery remains a bottleneck due to immune responses to viral vectors, limitations in the efficiency of lipid nanoparticles in the heart, and the precision required to target cardiomyocytes or conduction cells, all of which slow progress. Future work will depend as much on technical refinement as on navigating ethical, regulatory, and societal concerns.
