Translation of New and Emerging Therapies for Genetic Cardiomyopathies

Abstract

The primary etiology of a diverse range of cardiomyopathies is now understood to be genetic, creating a new paradigm for targeting treatments on the basis of the underlying molecular cause. This review provides a genetic and etiologic context for the traditional clinical classifications of cardiomyopathy, including molecular subtypes that may exhibit differential responses to existing or emerging treatments. The authors describe several emerging cardiomyopathy treatments, including gene therapy, direct targeting of myofilament function, protein quality control, metabolism, and others. The authors discuss advantages and disadvantages of these approaches and indicate areas of high potential for short- and longer term efficacy.

Keywords: AAV, adeno-associated virus; ACM, arrhythmogenic cardiomyopathy; ARVC, arrhythmogenic right ventricular cardiomyopathy; ATPase, adenosine triphosphatase; DCM, dilated cardiomyopathy; DMD, Duchenne muscular dystrophy; DNA, DNA; DSP, desmoplakin; FDA, U.S. Food and Drug Administration; GRT, gene replacement therapy; GST, gene silencing therapy; HCM, hypertrophic cardiomyopathy; HR, homologous recombination; LNP, lipid nanoparticle; LVOT, left ventricular outflow tract; RNA, RNA; TTR, transthyretin; arrhythmogenic cardiomyopathy; dilated cardiomyopathy; genetics; hypertrophic cardiomyopathy; therapeutics.

Graphical abstract

Central Illustration

Existing and Emerging Therapies for Genetic Cardiomyopathies Existing therapies are limited largely to treatment of symptomatic patients with established disease and adverse ventricular remodeling. Emerging therapies would target early effects of genetic and environmental triggers, ideally before disease is fully manifest. These include genetic therapies and modulators of primary and secondary disease pathways. Figure created with biorender.com. ACM = arrhythmogenic cardiomyopathy; DCM = dilated cardiomyopathy; HCM = hypertrophic cardiomyopathy.

Figure 1

Gene Therapy With the gene replacement strategy, a wild-type gene is expressed by a promoter within a viral vector to replace gene function in the setting of a loss-of-function variant. Gene silencing is typically used to reduce expression of a mutant gene (referred to as allele-specific silencing) and applies primarily to missense variants (ie, single-nucleotide substitutions) that alter protein function. For direct genome editing, using CRISPR-Cas9, a targeted DNA cleavage can be directed to a precise location in the genome determined by the unique sequence of a guide RNA (RNA). Figure created with biorender.com. AAV = adeno-associated virus; mRNA = messenger RNA.

Figure 2

Myosin Modulators Omecamtiv was developed to improve contractile force for treatment of dilated cardiomyopathy. The mechanisms of this drug are complicated, but increased attachment time of myosin cross bridges to actin serves to activate the thin filament and increase contractility. Conversely, mavacamten and similar compounds were developed to decrease contractile force for treatment of hypertrophic cardiomyopathy. These compounds act by decreasing myosin ATPase activity, resulting in the formation of fewer myosin-actin cross bridges. Figure created with biorender.com.

Figure 3

Cardiac TTR Amyloidosis Therapies Gene silencing therapy, using a silencing RNA packaged in lipid nanoparticle and delivered to the liver, has been shown to be effective at treating the polyneuropathy associated with transthyretin (TTR) amyloidosis. Stabilization of the TTR tetramer with tafamidis is effective in treating both polyneuropathy and cardiomyopathy. Monoclonal antibodies to extract TTR amyloid deposits from tissues are in clinical trials. Figure created with biorender.com.