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Targeting the sarcomere in inherited cardiomyopathies

Abstract

Variants in >12 genes encoding sarcomeric proteins can cause various cardiomyopathies. The two most common are hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Current therapeutics do not target the root causes of these diseases, but attempt to prevent disease progression and/or to manage symptoms. Accordingly, novel approaches are being developed to treat the cardiac muscle dysfunction directly. Challenges to developing therapeutics for these diseases include the diverse mechanisms of pathogenesis, some of which are still being debated and defined. Four small molecules that modulate the myosin motor protein in the cardiac sarcomere have shown great promise in the settings of HCM and DCM, regardless of the underlying genetic pathogenesis, and similar approaches are being developed to target other components of the sarcomere. In the setting of HCM, mavacamten and aficamten bind to the myosin motor and decrease the ATPase activity of myosin. In the setting of DCM, omecamtiv mecarbil and danicamtiv increase myosin activity in cardiac muscle (but omecamtiv mecarbil decreases myosin activity in vitro). In this Review, we discuss the therapeutic strategies to alter sarcomere contractile activity and summarize the data indicating that targeting one protein in the sarcomere can be effective in treating patients with genetic variants in other sarcomeric proteins, as well as in patients with non-sarcomere-based disease.

Key points

  • Variants in genes encoding sarcomeric proteins are a leading cause of cardiomyopathies that are characterized by protein-specific molecular mechanisms of disease.

  • Sarcomeric proteins can be targeted by small molecules to directly modulate contractile function in cardiac muscle.

  • Small molecules that are targeted to the myosin heavy chain modulate enzymatic activity and/or availability of the myosin motor, leading to an increase or decrease in force production.

  • Small molecules that target the myosin heavy chain, such as mavacamten and aficamten, can act via distinct molecular mechanisms that lead to altered myosin function.

  • Sarcomere pharmacology suggests that small molecules targeting a specific sarcomeric protein will be effective even in patients with a causal variant in a gene encoding another sarcomeric protein.

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Fig. 1: The cardiac sarcomere and its components.
Fig. 2: The functional states of myosin.
Fig. 3: The molecular mechanisms of myosin modulation by targeted small molecules.

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S.J.L. is currently a part-time employee of Edgewise Therapeutics. L.A.L. is on the scientific advisory board and has a sponsored research agreement with Bristol Myers Squibb/MyoKardia. C.C. declares no competing interests.

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Lehman, S.J., Crocini, C. & Leinwand, L.A. Targeting the sarcomere in inherited cardiomyopathies. Nat Rev Cardiol 19, 353–363 (2022). https://doi.org/10.1038/s41569-022-00682-0

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