Myosin inhibitor (MYK461) and gene therapy remedied relaxation defects in an iPSC model of TNNI3-mutated restrictive cardiomyopathy, and MYK461 normalized ejection fraction in a mouse model.
Does myosin inhibitor (MYK461) or gene therapy improve relaxation defects in preclinical models of restrictive cardiomyopathy caused by TNNI3 mutation?
Myosin inhibition or gene therapy may offer a potential targeted treatment for restrictive cardiomyopathy caused by TNNI3 mutations by rescuing relaxation defects.
Abstract Twins developed severe heart failure and died two weeks later when they were just nine months old. Clinical examinations indicated that they suffered restrictive cardiomyopathy (RCM), and the whole exome sequencing identified a novel heterozygous de novo mutation in TNNI3. To explore molecular mechanisms underlying the TNNI3 mutation, we used induced pluripotent stem cell (iPSC) and mouse models. First, we performed a contraction analysis with iPSC-derived cardiomyocytes and revealed a relaxation delay when cells expressed the mutated TNNI3. We generated a mouse model harboring the orthologous mutations using CRISPR/Cas9. Homozygous mutant mice died between postnatal days 10 to 14. Heterozygous mice survived more than 1.5 years but showed a progressive reduction of left ventricular relaxation with increased ejection fraction, phenocopying RCM. Structure information indicated that the mutated residue may hinder TNNI3 function to cover the myosin-binding pocket of actin. We, therefore, hypothesized that the mutation led to over-contraction even at the low cytosolic calcium ion, noncontracting phase, because of the failure to block myosin binding to actin. We next examined if myosin inhibitor (MYK461) or gene therapy can rescue relaxation failure, and both remedied the relaxation defects in the iPSC-derived cardiomyocyte model. We finally tested if myosin inhibitor could increase left ventricular relaxation. Tentative results suggested myosin inhibitor mildly rescued left ventricular relaxation and normalized ejection fraction. This study revealed the molecular mechanisms of RCM caused by TNNI3 mutation and offers a potential treatment for RCM.
Uosaki et al. (Sat,) conducted a other in Restrictive cardiomyopathy (n=2). Myosin inhibitor (MYK461) and gene therapy was evaluated on Left ventricular relaxation and ejection fraction. Myosin inhibitor (MYK461) and gene therapy remedied relaxation defects in an iPSC model of TNNI3-mutated restrictive cardiomyopathy, and MYK461 normalized ejection fraction in a mouse model.