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<p>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 <i>MYBPC3</i>). 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 Ca<sup>2+</sup> sensitivity and a favored ON structural state of myosin. Even though these pathomechanisms do not overlap with those triggered by truncating <i>MYBPC3</i> 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 <i>MYBPC3</i> variants regardless of their primary pathomechanisms.</p>

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

  • 期刊论文

  • 发表日期：

    2026年7月7日

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  • Laura Sen-Martín,
  • Ángel Fernández-Trasancos,
  • Miguel Á. López-Unzu,
  • Agata Bak,
  • Magdalena Zafra-Castellano,
  • Rajiven Srikantharajah,
  • Divya Pathak,
  • Annika Klotz,
  • Michel N. Kuehn,
  • Alessia Ferrarini,
  • Verónica Labrador-Cantarero,
  • David Sánchez-Ortiz,
  • María Rosaria Pricolo,
  • Natalia Vicente,
  • Diana Velázquez-Carreras,
  • Lucía Sánchez-García,
  • Jon Sicilia,
  • José Ángel Nicolás-Ávila,
  • María Sánchez-Díaz,
  • Saskia Schlossarek,
  • Lorena Cussó,
  • Manuel Desco,
  • María Villalba-Orero,
  • Gabriela Guzmán-Martínez,
  • Enrique Calvo,
  • Roberto Barriales-Villa,
  • Jesús Vázquez,
  • Fátima Sánchez-Cabo,
  • Andrés Hidalgo,
  • Pieter P. de Tombe,
  • Lucie Carrier,
  • James A. Spudich,
  • Kathleen M. Ruppel,
  • Florian Weinberger,
  • Olivier Cazorla,
  • Anthony L. Hessel,
  • Jorge Alegre-Cebollada

摘要

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.