A computational method for identifying an optimal combination of existing drugs to repair the action potentials of SQT1 ventricular myocytes

Mutations are known to cause perturbations in essential functional features of integral membrane proteins, including ion channels. Even restricted or point mutations can result in substantially changed properties of ion currents. The additive effect of these alterations for a specific ion channel can result in significantly changed properties of the action potential (AP). Both AP shortening and AP prolongation can result from known mutations, and the consequences can be life-threatening. Here, we present a computational method for identifying new drugs utilizing combinations of existing drugs. Based on the knowledge of theoretical effects of existing drugs on individual ion currents, our aim is to compute optimal combinations that can ‘repair’ the mutant AP waveforms so that the baseline AP-properties are restored. More specifically, we compute optimal, combined, drug concentrations such that the waveforms of the transmembrane potential and the cytosolic calcium concentration of the mutant cardiomyocytes (CMs) becomes as similar as possible to their wild type counterparts after the drug has been applied. In order to demonstrate the utility of this method, we address the question of computing an optimal drug for the short QT syndrome type 1 (SQT1). For the SQT1 mutation N588K, there are available data sets that describe the effect of various drugs on the mutated K+ channel. These published findings are the basis for our computational analysis which can identify optimal compounds in the sense that the AP of the mutant CMs resembles essential biomarkers of the wild type CMs. Using recently developed insights regarding electrophysiological properties among myocytes from different species, we compute optimal drug combinations for hiPSC-CMs, rabbit ventricular CMs and adult human ventricular CMs with the SQT1 mutation. Since the ‘composition’ of ion channels that form the AP is different for the three types of myocytes under consideration, so is the composition of the optimal drug.Author summary: Poly-pharmacology (using multiple drugs to treat disease) has been proposed for improving cardiac anti-arrhythmic therapy for at least two decades. However, the specific arrhythmia contexts in which polytherapy is likely to be both safe and effective have remained elusive. Type 1 short QT syndrome (SQT1) is a rare form of cardiac arrhythmia that results from mutations to the human Ether-á-go-go Related Gene (hERG) potassium channel. Functionally, these mutations are remarkably consistent in that they permit the channel to open earlier during each heart beat. While hundreds of compounds are known to inhibit hERG channels, the specific effect of SQT1 mutations that allows for early channel opening also limits the ability of most of those compounds to correct SQT1 dysfunction. Here, we have applied a suite of ventricular cardiomyocyte computational models to ask whether polytherapy may offer a more effective therapeutic strategy in SQT1, and if so, what the likely characteristics of that strategy are. Our analyses suggest that simultaneous induction of late sodium current and partial hERG blockade offers a promising strategy. While no activators of late sodium current have been clinically approved, several experimental compounds are available and may provide a basis for interrogating this strategy. The method presented here can be used to compute optimal drug combinations provided that the effect of each drug on every relevant ion channel is known.