Human iPSC-CMs and in-silico technologies define mechanisms and accelerate targeted pharmacogenetics in hypertrophic cardiomyopathy

Margara, F.; Psaras, Y.; Wang, Z. J.; Schmid, M.; Doste, R.; Garfinkel, A.; Repetti, G. G.; Seidman, J.; Seidman, C.; Rodriguez, B.; Toepfer, C. N.; Bueno-Orovio, A.

doi:10.1101/2022.06.08.495324

bioRxiv · 10.1101/2022.06.08.495324

Human iPSC-CMs and in-silico technologies define mechanisms and accelerate targeted pharmacogenetics in hypertrophic cardiomyopathy

Margara, F.·Psaras, Y.·Wang, Z. J.·Schmid, M.·Doste, R.·Garfinkel, A.·Repetti, G. G.·Seidman, J.·Seidman, C.·Rodriguez, B.·Toepfer, C. N.·Bueno-Orovio, A.

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Abstract

Cardiomyopathies have unresolved genotype-phenotype relationships and lack disease-specific treatments. Here we identify genotype-specific pathomechanisms and therapeutic targets combining experimental hiPSC-CM modelling and human-based cardiac electromechanical in-silico modelling and simulation bridging from specific mutations to clinical biomarkers. We select hypertrophic cardiomyopathy as a challenge for this approach and study genetic variations that mutate proteins of the thick (MYH7R403Q/+) and thin filaments (TNNT2R92Q/+, TNNI3R21C/+) of the cardiac sarcomere. We show that destabilisation of myosin super relaxation drives disease in MYH7R403Q/+ with secondary effects on thin filament activation, which are corrected by Mavacamten. Thin filament variants TNNT2R92Q/+ and TNNI3R21C/+ share calcium regulation-related pathomechanisms, for which Mavacamten provides incomplete salvage. 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.

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Margara, F., Psaras, Y., Wang, Z. J., Schmid, M., Doste, R., Garfinkel, A., Repetti, G. G., Seidman, J., Seidman, C., Rodriguez, B., Toepfer, C. N., Bueno-Orovio, A.. 2022-06-11. Human iPSC-CMs and in-silico technologies define mechanisms and accelerate targeted pharmacogenetics in hypertrophic cardiomyopathy. https://doi.org/10.1101/2022.06.08.495324

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