Mechanism based therapies enable personalised treatment of hypertrophic cardiomyopathy
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-sil...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Springer Nature
2022
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| _version_ | 1826309714277826560 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Margara, F |
| collection | OXFORD |
| description | 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 (<i>MYH7</i><sup>R403Q/+</sup>) and thin filaments (<i>TNNT2</i><sup>R92Q/+</sup>, <i>TNNI3</i><sup>R21C/+</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<sup>R403Q/+</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<sup>R403Q/+</sup> phenotype in agreement with hiPSC-CM experiments. Our in-silico model predicts that the thin filament variants TNNT2<sup>R92Q/+</sup> and TNNI3<sup>R21C/+</sup> display altered calcium regulation as central pathomechanism, for which Mavacamten provides incomplete salvage, which we have corroborated in TNNT2<sup>R92Q/+</sup> and TNNI3<sup>R21C/+</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. |
| first_indexed | 2024-03-07T07:39:50Z |
| format | Journal article |
| id | oxford-uuid:bb852b40-527f-4a71-b8fb-e9c2678de186 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:39:50Z |
| publishDate | 2022 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:bb852b40-527f-4a71-b8fb-e9c2678de1862023-04-14T16:06:07ZMechanism based therapies enable personalised treatment of hypertrophic cardiomyopathyJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:bb852b40-527f-4a71-b8fb-e9c2678de186EnglishSymplectic ElementsSpringer Nature2022Margara, FPsaras, YWang, ZJSchmid, MDoste, RGarfinkel, ACRepetti, GGSeidman, JGSeidman, CERodriguez, BToepfer, CNBueno-Orovio, ACardiomyopathies 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 (<i>MYH7</i><sup>R403Q/+</sup>) and thin filaments (<i>TNNT2</i><sup>R92Q/+</sup>, <i>TNNI3</i><sup>R21C/+</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<sup>R403Q/+</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<sup>R403Q/+</sup> phenotype in agreement with hiPSC-CM experiments. Our in-silico model predicts that the thin filament variants TNNT2<sup>R92Q/+</sup> and TNNI3<sup>R21C/+</sup> display altered calcium regulation as central pathomechanism, for which Mavacamten provides incomplete salvage, which we have corroborated in TNNT2<sup>R92Q/+</sup> and TNNI3<sup>R21C/+</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. |
| spellingShingle | 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 Mechanism based therapies enable personalised treatment of hypertrophic cardiomyopathy |
| title | Mechanism based therapies enable personalised treatment of hypertrophic cardiomyopathy |
| title_full | Mechanism based therapies enable personalised treatment of hypertrophic cardiomyopathy |
| title_fullStr | Mechanism based therapies enable personalised treatment of hypertrophic cardiomyopathy |
| title_full_unstemmed | Mechanism based therapies enable personalised treatment of hypertrophic cardiomyopathy |
| title_short | Mechanism based therapies enable personalised treatment of hypertrophic cardiomyopathy |
| title_sort | mechanism based therapies enable personalised treatment of hypertrophic cardiomyopathy |
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