Patient-Specific Inducible Pluripotent Stem Cells Reveal Mechanism of Personalized Therapy for an Inherited Cardiac Arrhythmia

We report a study using inducible pluripotent stem cells (iPSCs) designed to unravel the mechanistic basis for resistance to previously prescribed gene-specific therapy for a patient carrying a Long QT Syndrome variant 3 (LQT3) mutation. The previous therapy, treatment with the Na+ channel blocker mexiletine, had been based on previous heterologous expression studies. In contrast to previous predictions arrhythmias in the proband have not been controlled by mexiletine, which has had a limited therapeutic dose range because of increased clinical risk found at high doses. The proband harbors a de novoSCN5A mutation (F1473C) and is heterozyous in KCNH2 (K897/T897). Both parents lack the SCNA5 mutation and each is homozygous for either T897 or K897 KCNH2. Cardiomyocytes (hiPSC-CMs) were derived from hiPSCs produced by lentiviral reprograming of skin fibroblasts. Whole-cell patch clamp was performed on single hiPSC-CMs from each family member and confirmed dysfuntional Na+ channel inactivation in cells from the proband but neither parent which was corrected by mexiletine (50 μM). However this same mexiletine concentration was found to also have sginficant off-target block of L-type calcium and IKr potassium channels, which may explain the patient's suboptimal response to the therapeutic regimen and limited useful therapeutic dose range of the drug. Instead of raising drug concentration we show that increased heart rate, which in the patient is controlled by an implantable cardioverter-defibrillator (ICD), effetively and markedly inhibits dysfunctional Na+ channel activity in these cells and has markedly suppressed arrhythmic events in the proband. These results demonstrate the power and utility of iPSCs in detecting mechanisms of disease and optimizing its treatment in patient-specific manner.