Targeting the sarcomere in inherited cardiomyopathies

Area of Science:

• Cardiovascular Medicine
• Molecular Cardiology
• Genetic Diseases

Background:

• Genetic variants in sarcomeric proteins are a primary cause of cardiomyopathies, including hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM).
• Current treatments for HCM and DCM primarily manage symptoms and slow disease progression, rather than addressing the underlying molecular pathology.
• Developing effective therapeutics is challenging due to the diverse and sometimes unclear pathogenic mechanisms involved in these cardiac conditions.

Purpose of the Study:

• To review therapeutic strategies aimed at modulating sarcomere contractile activity for cardiomyopathies.
• To summarize the efficacy of small molecules targeting sarcomeric proteins in treating HCM and DCM.
• To highlight the potential of targeting one sarcomeric component to treat diseases caused by variants in other sarcomeric proteins or non-sarcomeric factors.

Main Methods:

• Review of existing literature on small molecule therapeutics targeting sarcomeric proteins.
• Analysis of data on drugs modulating myosin motor protein activity in the context of HCM and DCM.
• Discussion of therapeutic approaches targeting other sarcomeric components.

Main Results:

• Four small molecules (mavacamten, aficamten, omecamtiv mecarbil, danicamtiv) targeting cardiac myosin have demonstrated significant therapeutic potential in preclinical and clinical studies.
• Mavacamten and aficamten reduce myosin ATPase activity in HCM, while omecamtiv mecarbil and danicamtiv aim to increase myosin activity in DCM.
• Evidence suggests that targeting a single sarcomeric protein can yield benefits across various genetic cardiomyopathies and even in non-sarcomeric forms of heart disease.

Conclusions:

• Modulating sarcomere protein function, particularly cardiac myosin, represents a promising therapeutic avenue for HCM and DCM.
• Sarcomere-targeted therapies offer a potential disease-modifying approach irrespective of the specific genetic mutation.
• Future research should focus on optimizing these sarcomere-based strategies for broader application in managing cardiomyopathies.