Mavacamten shows broad benefit in human and mouse models of MYBPC3-related hypertrophic cardiomyopathy

Abstract

Mavacamten is a targeted treatment for hypertrophic cardiomyopathy, a disease caused by genetic variants affecting mainly sarcomeric myosin and its regulator cardiac myosin-binding protein C (cMyBP-C, encoded by MYBPC3). Here we generate knock-in mice including missense pathogenic variant cMyBP-C p.R502W, which unlike carriers of cMyBP-C truncations, develop pathogenic myocardial remodeling with preserved cMyBP-C levels and localization. Mechanistically, R502W reduces cMyBP-C–myosin affinity and generates sarcomere hypercontractility due to increased Ca2+ sensitivity and a favored ON structural state of myosin. Even though these pathomechanisms do not overlap with those triggered by truncating MYBPC3 variants, mavacamten blunts myocardial remodeling both in R502W and cMyBP-C-deficient hearts, correlating with the drug’s ability to restore OFF myosin in R502W sarcomeres. In R502W human engineered heart tissues, mavacamten also opposes hypercontractility. Hence, our results indicate that mavacamten is effective in treating hypertrophic cardiomyopathy caused by both truncating and missense MYBPC3 variants regardless of their primary pathomechanisms. Sen-Martín et al. demonstrate that mavacamten exerts therapeutic benefit in hypertrophic cardiomyopathy caused by both missense and truncating MYBPC3 variants by reducing hypercontractility and myocardial remodeling through normalization of myosin activity.