Mechanism based therapies enable personalised treatment of hypertrophic cardiomyopathy
Margara F., Psaras Y., Wang ZJ., Schmid M., Doste R., Garfinkel AC., Repetti GG., Seidman JG., Seidman CE., Rodriguez B., Toepfer CN., BUENO OROVIO A.
<jats:title>Abstract</jats:title><jats:p>Cardiomyopathies have unresolved genotype–phenotype relationships and lack disease-specific treatments. Here we provide a framework to identify genotype-specific pathomechanisms and therapeutic targets to accelerate the development of precision medicine. We use human cardiac electromechanical in-silico modelling and simulation which we validate with experimental hiPSC-CM data and modelling in combination with clinical biomarkers. We select hypertrophic cardiomyopathy as a challenge for this approach and study genetic variations that mutate proteins of the thick (<jats:italic>MYH7</jats:italic><jats:sup>R403Q/+</jats:sup>) and thin filaments (<jats:italic>TNNT2</jats:italic><jats:sup>R92Q/+</jats:sup>, <jats:italic>TNNI3</jats:italic><jats:sup>R21C/+</jats:sup>) of the cardiac sarcomere. Using in-silico techniques we show that the destabilisation of myosin super relaxation observed in hiPSC-CMs drives disease in virtual cells and ventricles carrying the MYH7<jats:sup>R403Q/+</jats:sup> variant, and that secondary effects on thin filament activation are necessary to precipitate slowed relaxation of the cell and diastolic insufficiency in the chamber. In-silico modelling shows that Mavacamten corrects the MYH7<jats:sup>R403Q/+</jats:sup> phenotype in agreement with hiPSC-CM experiments. Our in-silico model predicts that the thin filament variants TNNT2<jats:sup>R92Q/+</jats:sup> and TNNI3<jats:sup>R21C/+</jats:sup> display altered calcium regulation as central pathomechanism, for which Mavacamten provides incomplete salvage, which we have corroborated in TNNT2<jats:sup>R92Q/+</jats:sup> and TNNI3<jats:sup>R21C/+</jats:sup> hiPSC-CMs. We define the ideal characteristics of a novel thin filament-targeting compound and show its efficacy in-silico. We demonstrate that hybrid human-based hiPSC-CM and in-silico studies accelerate pathomechanism discovery and classification testing, improving clinical interpretation of genetic variants, and directing rational therapeutic targeting and design.</jats:p>