An FDA-approved drug structurally and phenotypically corrects the K210del mutation in genetic cardiomyopathy models.

Summary

The authors solved the crystal structure of the troponin complex carrying the TNNT2 K210del mutation, revealing S69 distortion in TnC and calcium discoordination. Structure-guided repurposing identified risedronate, which restored the mutant structure, normalized force in K210del patient iPSC-cardiomyocytes, improved calcium sensitivity in skinned muscle, and normalized LVEF in K210del mice.

Key Findings

• K210del in TNNT2 induces an allosteric shift that distorts TnC S69 and disrupts calcium coordination.
• Risedronate cocrystallized with the mutant troponin complex restores S69 configuration and Ca2+ coordination.
• Risedronate normalizes force generation in K210del patient iPSC-derived cardiomyocytes.
• Skinned papillary muscles from K210del mice show improved calcium sensitivity with risedronate.
• Systemic risedronate administration normalizes left ventricular ejection fraction in K210del mice.

Clinical Implications

While preclinical, these results support clinical exploration of risedronate as a mutation-specific therapy for TNNT2 K210del DCM and provide a generalizable framework for structure-guided drug repurposing in genetic cardiomyopathies.

Limitations

• Findings are mutation-specific (TNNT2 K210del) and may not generalize to other DCM mutations.
• Preclinical study without human clinical trial data; dosing, safety, and efficacy in patients remain unknown.

Future Directions

Phase 1/2 trials to assess safety and pharmacodynamics of risedronate in TNNT2 K210del carriers; expansion of structure-guided screens to other sarcomeric mutations; long-term efficacy and off-target assessments.