Gene-based Therapies for Genetic Cardiomyopathies: Molecular Medicine for Heart Disease

Pathogenic genetic alterations are a well-recognized mechanism in cardiomyopathies. As such, genetic testing has become an integral component of the diagnostic pathway for cardiomyopathy. Subsequent developments in gene-specific therapies have advanced precision medicine by enabling direct targeting of pathogenic genetic variants, demonstrating promise as the ultimate therapy for cardiomyopathy. Gene therapy can be categorized into three main approaches: gene replacement, gene silencing, and direct genome editing. Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology laid the foundation for genome editing, followed by the development of base editors and prime editors. These tools allow for single-base changes to address point mutations, as well as target insertion, deletion, transition, and transverse mutations. There have been equally essential advancements in the development of gene delivery vectors. These include viral vectors, especially the novel capsids of adeno-associated virus, due to their lower immunogenicity and better transduction efficiency compared to other viral vectors; virus-like particles that contain self-assembling virus-derived structures without the genetic material; and non-viral nanoparticles that can be polymeric, inorganic, or, most commonly, lipid nanoparticles. Antisense oligonucleotides have also emerged as part of the toolkit to allow for exon skipping in large genes with pathogenic variants. All these gene therapy and delivery vector approaches come with their own advantages and safety considerations. In this review, we describe the genetic basis and expanding research on gene-based therapies for patients with hypertrophic cardiomyopathy, dilated cardiomyopathy, muscular dystrophy-related cardiomyopathies, and transthyretin amyloidosis.