Key result
CRISPR/Cas9 shows preclinical promise for correcting inherited channelopathies, though translational hurdles remain.
Why the study?
Current therapies for inherited cardiac channelopathies reduce risk but fail to correct the underlying genetic substrate, creating an urgent need for curative strategies.
CRISPR/Cas9 gene editing shows promise in preclinical models for correcting the underlying genetic substrate of inherited cardiac channelopathies, though significant translational challenges remain.
Clinical application remains distant for inherited arrhythmias; leaves open the need for rigorous safety and delivery.
Inherited cardiac channelopathies, including long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia, are major causes of arrhythmic morbidity and sudden cardiac death in young individuals. Current therapies, such as pharmacologic agents, implantable cardioverter-defibrillators, and lifestyle modifications, reduce risk but fail to correct the underlying genetic substrate, creating an urgent need for curative strategies. CRISPR/Cas9 genome editing has emerged as a transformative platform with the potential to directly repair pathogenic variants. Recent advances in base and prime editing, together with novel viral and nonviral delivery platforms, have enabled precise correction of disease-causing mutations in preclinical models. Proof-of-concept studies using animal models and patient-derived iPSC-cardiomyocytes demonstrate restoration of electrophysiologic stability, suppression of arrhythmias, and durable functional benefit. Nevertheless, translational challenges remain, including off-target effects, delivery barriers, immune responses, scalability, and ethical considerations. Ongoing innovations-such as engineered nucleases, improved delivery vectors, immunogenicity mitigation strategies, and integration of artificial intelligence for personalized guide design-are expected to accelerate clinical translation. This review synthesizes current knowledge on CRISPR-based strategies for inherited channelopathies, highlighting both the promise and limitations of gene editing as a path toward durable, disease-modifying therapies capable of preventing sudden cardiac death.
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Tran et al. (2025) conducted a review in Inherited cardiac channelopathies. CRISPR/Cas9-based gene editing was evaluated. CRISPR/Cas9-based gene editing demonstrates potential for correcting pathogenic variants in inherited channelopathies in preclinical models, though significant translational challenges remain.
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