Abstract
Classical drug development is compromised by considerable clinical failure of promising drug candidates after decades of costly preclinical work. Failure can be because of previously unrecognized safety concerns or more commonly lack of clinical efficacy. Classical drug discovery and safety pharmacology programs rely heavily on well-established in vitro and preclinical animal models. The availability of human pluripotent stem cells and the possibility to direct them into any somatic cell type suggest that a paradigm shift in drug development may be possible and timely, with the opportunity to test safety and efficacy of candidate drugs on the human target cells and tissue. However, there is considerable uncertainty as to whether human models would only qualify as replacement for well-established tools or add substantially more information to the preclinical data package, to facilitate translation of more promising drug candidates into clinical practice. This chapter provides an overview of tissue-engineered macro-scale heart muscle models for applications in drug discovery and safety pharmacology.
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Abbreviations
- ABCF-I :
-
Activin A, BMP4, CHIR, and FGF2 followed by IWP4
- ACTN2:
-
Sarcomeric alpha-actinin 2
- BMP4:
-
Bone morphogenetic protein 4
- CHIR99021:
-
6-((2-((4-(2,4-Dichlorophenyl)-5-(4-methyl-1H-imidazol-2-yl)pyrimidin-2-yl)amino)ethyl)amino)nicotinonitrile
- CiPA:
-
Comprehensive in vitro proarrhythmia assay
- CSA:
-
Cross-sectional area
- DKK1:
-
Dickkopf-related protein 1
- EB:
-
Embryoid body
- EHM:
-
Engineered heart muscle or engineered human myocardium
- EHT:
-
Engineered heart tissue
- ESC:
-
Embryonic stem cells
- FBS:
-
Fetal bovine serum
- FGF2:
-
Fibroblast growth factor-2
- FOC:
-
Force of contraction
- FT:
-
Force transducer
- GiWi :
-
Staged GSK and Wnt inhibition
- GSK:
-
Glycogen synthase kinase
- hERG:
-
Ether-à-go-go-related gene-related channels
- hvCOC :
-
Human ventricular cardiac organoid chambers
- hvCTS :
-
Human ventricular cardiac tissue strips
- ICH :
-
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use
- iPSC:
-
Induced pluripotent stem cells
- IWP2:
-
Inhibitor of Wnt processing and secretion 2 – N-(6-methyl-2-benzothiazolyl)-2-[(3,4,6,7-tetrahydro-4-oxo-3-phenylthieno[3,2-d]pyrimidin-2-yl)thio]-acetamide
- IWP4:
-
Inhibitor of Wnt processing and secretion 4 – N-(6-methyl-2-benzothiazolyl)-2-[[3,4,6,7-tetrahydro-3-(2-methoxyphenyl)-4-oxothieno[3,2-d]pyrimidin-2-yl]thio]-acetamide
- KLF4:
-
Krüppel-like factor 4 (reprogramming factor)
- KY02111:
-
N-(6-Chloro-2-benzothiazolyl)-3,4-dimethoxy-benzenepropanamide
- MaPS:
-
Macro-physiological systems
- MiPS:
-
Micro-physiological systems
- MYC:
-
Myelocytomatosis proto-oncogene (reprogramming factor)
- MYH7:
-
Myosin heavy chain beta
- NT-proBNP:
-
N-terminal pro-B-type natriuretic peptide
- OCT4:
-
Octamer-binding transcription factor 4 (reprogramming factor)
- PB:
-
Pole bending
- SOX2:
-
Sex-determining region Y-box 2 (reprogramming factor)
- TdP :
-
Torsade de pointes
- TNNT2:
-
Cardiac muscle troponin T
- VEGFA:
-
Vascular endothelial growth factor-A
- Wnt:
-
Wingless and Int-1
- Wnt-C59:
-
Inhibitor of mammalian porcupine acyltransferase activity – 4-(2-methyl-4-pyridinyl)-N-[4-(3-pyridinyl)phenyl]benzeneacetamide
- XAV939:
-
3,5,7,8-Tetrahydro-2-[4-(trifluoromethyl)phenyl]-4H-thiopyrano[4,3-d]pyrimidin-4-one
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Acknowledgment
This chapter focusses on studies using human heart MaPS model, and thus references are, with few exceptions to provide historical background, restricted to human models.
Financial Support
W.H.Z. is supported by the DZHK (German Center for Cardiovascular Research), the Federal Ministry for Science and Education (BMBF), the German Research Foundation (SFB 1002 TP C04/S01; MBExC), and the Fondation Leducq.
Conflict of Interest
W.H.Z. is listed as inventor on several filed and granted patents in the field of stem cell models and tissue engineering. W.H.Z. is founder and advisor of myriamed GmbH, which is offering stem cell technologies and tissue engineering-based drug screening services, and Repairon GmbH, which is developing engineered human myocardium for clinical applications in heart failure repair.
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Zimmermann, WH. (2020). Engineered Heart Muscle Models in Phenotypic Drug Screens. In: Schäfer-Korting, M., Stuchi Maria-Engler, S., Landsiedel, R. (eds) Organotypic Models in Drug Development. Handbook of Experimental Pharmacology, vol 265. Springer, Cham. https://doi.org/10.1007/164_2020_385
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