@article{62e97c738f1241d6bf04b5b2320465be,
title = "Reengineering an Antiarrhythmic Drug Using Patient hiPSC Cardiomyocytes to Improve Therapeutic Potential and Reduce Toxicity",
abstract = "Modeling cardiac disorders with human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes is a new paradigm for preclinical testing of candidate therapeutics. However, disease-relevant physiological assays can be complex, and the use of hiPSC-cardiomyocyte models of congenital disease phenotypes for guiding large-scale screening and medicinal chemistry have not been shown. We report chemical refinement of the antiarrhythmic drug mexiletine via high-throughput screening of hiPSC-CMs derived from patients with the cardiac rhythm disorder long QT syndrome 3 (LQT3) carrying SCN5A sodium channel variants. Using iterative cycles of medicinal chemistry synthesis and testing, we identified drug analogs with increased potency and selectivity for inhibiting late sodium current across a panel of 7 LQT3 sodium channel variants and suppressing arrhythmic activity across multiple genetic and pharmacological hiPSC-CM models of LQT3 with diverse backgrounds. These mexiletine analogs can be exploited as mechanistic probes and for clinical development.",
keywords = "arrhythmia, cardiomyocyte, disease modeling, drug development, electrophysiology, high-throughput screening, induced pluripotent stem cells, long QT syndrome, medicinal chemistry, mexiletine",
author = "McKeithan, {Wesley L.} and Feyen, {Dries A.M.} and Bruyneel, {Arne A.N.} and Okolotowicz, {Karl J.} and Ryan, {Daniel A.} and Sampson, {Kevin J.} and Franck Potet and Alex Savchenko and Jorge G{\'o}mez-Galeno and Michelle Vu and Ricardo Serrano and George, {Alfred L.} and Kass, {Robert S.} and Cashman, {John R.} and Mark Mercola",
note = "Funding Information: We thank J. Wu (Stanford Cardiovascular Institute, Stanford, CA) and the Stanford Biobank for the healthy donor hiPSC lines. We also thank B. Conklin (Gladstone Institute of Cardiovascular Disease) for the LQT3 SCN5A N406K hiPSC line and Tatiana Abramova (Northwestern University) for engineering and expressing mutant Na v 1.5 plasmid constructs. This research was made possible by grants from the National Institutes of Health (NIH R01HL113601 , R01HL130840 , R01HL141358 , P01HL141084 , and R21HL141019 to M.M.; U01 HL131914 to A.L.G.; and R01HL123483 to R.S.K.), the American Heart Association ( 9SFRN34820006 to A.L.G.), and the California Institute for Regenerative Medicine (CIRM grant TR4-06857 to J.R.C. and M.M.). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of CIRM or any other agency of the state of California. Flow cytometry and high-throughput screening services were supported by NIH P30CA030199 at the Sanford-Burnham-Prebys Medical Discovery Institute. This research was also supported by the Stanford Cardiovascular Institute and Stanford School of Medicine funds to M.M. D.A.M.F. was funded by the European Union {\textquoteright}s Horizon 2020 Research and Innovation Programme under Marie Sklodowska-Curie grant 708459 . M.M. gratefully acknowledges funding from the Joan and Sanford Weill Scholarship Endowment . Funding Information: We thank J. Wu (Stanford Cardiovascular Institute, Stanford, CA) and the Stanford Biobank for the healthy donor hiPSC lines. We also thank B. Conklin (Gladstone Institute of Cardiovascular Disease) for the LQT3 SCN5A N406K hiPSC line and Tatiana Abramova (Northwestern University) for engineering and expressing mutant Nav1.5 plasmid constructs. This research was made possible by grants from the National Institutes of Health (NIH R01HL113601, R01HL130840, R01HL141358, P01HL141084, and R21HL141019 to M.M.; U01 HL131914 to A.L.G.; and R01HL123483 to R.S.K.), the American Heart Association (9SFRN34820006 to A.L.G.), and the California Institute for Regenerative Medicine (CIRM grant TR4-06857 to J.R.C. and M.M.). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of CIRM or any other agency of the state of California. Flow cytometry and high-throughput screening services were supported by NIH P30CA030199 at the Sanford-Burnham-Prebys Medical Discovery Institute. This research was also supported by the Stanford Cardiovascular Institute and Stanford School of Medicine funds to M.M. D.A.M.F. was funded by the European Union's Horizon 2020 Research and Innovation Programme under Marie Sklodowska-Curie grant 708459. M.M. gratefully acknowledges funding from the Joan and Sanford Weill Scholarship Endowment. Conceptualization, W.L.M. K.J.O. D.A.R. R.S.K. J.R.C. and M.M.; Methodology, W.L.M. D.A.M.F. A.A.N.B. K.J.O. D.A.R. K.J.S. F.P. A.S. A.L.G. R.S.K. J.R.C. and M.M.; Investigation, W.L.M. D.A.M.F. A.A.N.B. K.J.O. D.A.R. K.J.S. F.P. A.S. J.G.-G. M.V. and R.S.; Writing ? Original Draft, W.L.M. D.A.M.F. A.L.G. R.S.K. J.R.C. and M.M.; Writing ? Review & Editing, all authors; Funding Acquisition, D.A.M.F. A.L.G. R.S.K. J.R.C. and M.M.; Supervision, A.L.G. R.S.K. J.R.C. and M.M. Human BioMolecular Research Institute has filed a patent application on mexiletine analogs, in which J.R.C. K.J.O. and D.A.R. are co-inventors. M.M. serves on the scientific advisory board of Vala Sciences, which manufactures a high-content instrument used in these studies. A.L.G. serves on a scientific advisory board for cardiometabolic diseases at Amgen, Inc. The other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = nov,
day = "5",
doi = "10.1016/j.stem.2020.08.003",
language = "English (US)",
volume = "27",
pages = "813--821.e6",
journal = "Cell Stem Cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "5",
}
