Toward CRISPR Therapies for Cardiomyopathies

Genetic cardiomyopathies are a common cause of heart failure and sudden death. Despite an understanding of their underlying genetics, effective long-term therapy remains an unmet medical need. The recent advent of gene editing technologies provides a promising therapeutic opportunity for permanent correction of disease-causing mutations. Mutations in genes encoding cardiac structural proteins such as dystrophin, titin, and β-myosin heavy chain represent attractive targets for therapeutic gene editing. Although gene therapy can replace a mutant gene with a wild-type copy, this approach is limited to genes small enough to fit within viral vectors and is dependent on their continued expression. Gene editing strategies, in which a mutant gene is corrected within the context of its normal genetic milieu, allows for sustained expression of the edited gene. There are 3 general types of gene editing: gene disruption, reading frame restoration, and precise correction. Gene disruption can inactivate dominant negative or pathogenic gain-of-function mutations and eliminate the dysfunctional protein. Reading frame restoration can enable the expression of nonfunctional genes, often by reframing or skipping of out-of-frame exons, as is common for Duchenne muscular dystrophy (DMD). The recent development of precise correction strategies—using base or prime editors—allows the editing of pathogenic mutations.