Gene Editing Strategies (CRISPR) for Inherited Cardiomyopathies: Ethical, Technical and Clinical Review

Background: Inherited cardiomyopathies, such as hypertrophic, dilated and arrhythmogenic, are mediated by clearly defined genetic variants that are hard to combat using traditional therapy. Recent developments of gene-editing systems including CRISPRCas systems provide the opportunity to correct the causative mutations however, their translation elicits complicated ethical, technical and clinical issues. Objective: To overview the existing gene-editing options of inherited cardiomyopathies and assess their therapeutic potential, obstacles and available challenges of clinical use. Method: This was a review of preclinical research, initial therapeutic trials, genome-engineering system and bioethical models. It was emphasized on CRISPR-Cas9, base editing and prime-editing methods, as well as delivery methods such as AAV vectors and lipid nanoparticles. Moral considerations were done on the manipulation of germlines, off-target editing and long term consequences to society. Results: In animal and cellular models, gene editing demonstrated good possibilities in correcting pathogenic variants inMYH7, MYBPC3, LMNA and PKP2, and results were observed in improvement of myocardial structure and functioning. But there are still significant technical hurdles such as off-target effects, immune response to Cas proteins and limited efficacy of myocardial delivery. The ethical review pointed out the issues of germline edits, fair access and a long-term safety followup. Conclusion: Gene-editing technologies have a high potential of creating a new therapeutic alternative in inherited cardiomyopathies, considerable ethical, biological and translational challenges need to be overcome before clinical adoption. Additional streamline editing accuracy, delivery platform and regulatory authorities will be required to make them safe and responsible.