Myosin inhibitor reverses hypertrophic cardiomyopathy in genotypically diverse pediatric iPSC-cardiomyocytes to mirror variant correction

被引：2

作者：

Kinnear, Caroline ^{[1
]}

Said, Abdelrahman ^{[1
]}

Meng, Guoliang ^{[2
]}

Zhao, Yimu ^{[3
,4
]}

Wang, Erika Y. ^{[5
]}

Rafatian, Naimeh ^{[3
]}

Parmar, Neha ^{[1
]}

Wei, Wei ^{[2
]}

Billia, Filio ^{[4
,6
]}

Simmons, Craig A. ^{[3
,7
,8
]}

Radisic, Milica ^{[1
,3
,4
,9
,10
]}

Ellis, James ^{[1
,2
,4
,11
]}

Mital, Seema ^{[1
,2
,3
,4
,5
,6
,12
]}

机构：

[1] Hosp Sick Children, Program Genet & Genome Biol, Toronto, ON M5G 0A4, Canada

[2] Hosp Sick Children, Program Dev & Stem Cell Biol, Toronto, ON M5G 0A4, Canada

[3] Univ Toronto, Inst Biomed Engn, Toronto, ON M5S 3G9, Canada

[4] Univ Hlth Network, Toronto Gen Hosp Res Inst, Toronto, ON M5G 2C4, Canada

[5] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

[6] Ted Rogers Ctr Heart Res, Toronto, ON M5G 1M1, Canada

[7] Univ Toronto, Dept Mech & Ind Engn, Toronto, ON M5S 3G8, Canada

[8] Ted Rogers Ctr Heart Res, Translat Biol & Engn Program, Toronto, ON M5G 1M1, Canada

[9] Univ Toronto, Dept Chem Engn & Appl Chem, Toronto, ON M5S 3E5, Canada

[10] Univ Toronto, Terrence Donnelly Ctr Cellular & Biomol Res, Toronto, ON M5S 3E1, Canada

[11] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada

[12] Univ Toronto, Hosp Sick Children, Dept Pediat, Toronto, ON M5G 1X8, Canada

来源：

CELL REPORTS MEDICINE | 2024年 / 5卷 / 05期

基金：

美国国家卫生研究院; 加拿大健康研究院;

关键词：

PLURIPOTENT STEM-CELLS; CARDIAC TROPONIN; PATHOGENESIS; MUTATIONS; GENETICS;

D O I：

10.1016/j.xcrm.2024.101520

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Pathogenic variants in MYH7 and MYBPC3 account for the majority of hypertrophic cardiomyopathy (HCM). Targeted drugs like myosin ATPase inhibitors have not been evaluated in children. We generate patient and variant-corrected iPSC-cardiomyocytes (CMs) from pediatric HCM patients harboring single variants in MYH7 ( V606M ; R453C), ), MYBPC3 ( G148R ) or digenic variants ( MYBPC3 P955fs, , TNNI3 A157V). ). We also generate CMs harboring MYBPC3 mono- and biallelic variants using CRISPR editing of a healthy control. Compared with isogenic and healthy controls, variant-positive CMs show sarcomere disorganization, higher contractility, calcium transients, and ATPase activity. However, only MYH7 and biallelic MYBPC3 variant- positive CMs show stronger myosin-actin binding. Targeted myosin ATPase inhibitors show complete rescue of the phenotype in variant-positive CMs and in cardiac Biowires to mirror isogenic controls. The response is superior to verapamil or metoprolol. Myosin inhibitors can be effective in genotypically diverse HCM highlighting the need for myosin inhibitor drug trials in pediatric HCM.

引用

页数：23