Population-based mechanistic modeling allows for quantitative predictions of drug responses across cell types. (December 2018)

• Record Type: Journal Article
• Authors: Gong, Jingqi; Sobie, Eric
• Is Part Of: Npj systems biology and applications. Volume 4(2018)
• Page Start: 1
• Page End: 11
• Publication Date: 2018-12
• Subjects: Systems biology -- Periodicals; 570.113
• DOI: 10.1038/s41540-018-0047-2
• Languages: English
• ISSNs: 2056-7189

Abstract

Abstract Quantitative mismatches between human physiology and experimental models can be problematic for the development of effective therapeutics. When the effects of drugs on human adult cardiac electrophysiology are of interest, phenotypic differences with animal cells, and more recently stem cell-derived models, can present serious limitations. We addressed this issue through a combination of mechanistic mathematical modeling and statistical analyses. Physiological metrics were simulated in heterogeneous populations of models describing cardiac myocytes from adult ventricles and those derived from induced pluripotent stem cells (iPSC-CMs). These simulated measures were used to construct a cross-cell type regression model that predicts adult myocyte drug responses from iPSC-CM behaviors. We found that (1) quantitatively accurate predictions of responses to selective or non-selective ion channel blocking drugs could be generated based on iPSC-CM responses under multiple experimental conditions; (2) altering extracellular ion concentrations is an effective experimental perturbation for improving the model's predictive strength; (3) the method can be extended to predict and contrast drug responses in diseased as well as healthy cells, indicating a broader application of the concept. This cross-cell type model can be of great value in drug development, and the approach, which can be applied to other fields, represents an important strategy for overcoming experimental model limitations. Systems pharmacology: translation of drug responses across cell types The quantitative limitations of experimental models, which can impair the development of effective therapeutics, can be overcome through a combination of mechanistic simulations and statistical analysis. A team from Icahn School of Medicine at Mount Sinai led by Eric Sobie devised a computational method to quantitatively translate drug responses across cell types. The method involves mechanism-based simulations of heterogeneous populations combined with a multivariable regression model that translates between cell types. Simulation results presented in the study show that the response to a drug in one cell type can be predicted with quantitative accuracy from physiological recordings made in another cell type, as can differential drug responses observed in diseased compared with healthy cells. This methodology can be used in drug development to better predict clinical responses based on experiments performed in preclinical models.