Background: The KCNH2-encoded Kv11.1 (hERG) potassium channel is a critical regulator of the cardiomyocyte’s (CM) action potential duration (APD). The majority of type 2 long QT syndrome (LQT2) stems from KCNH2 mutations that are trafficking defective. Recently, the FDA-approved cystic fibrosis protein trafficking chaperone, lumacaftor (LUM), has been proposed as a novel therapy for patients with LQT2.
Objective: To test the efficacy of LUM treatment in patient-specific iPSC-CMs derived from patients with known LQT2 trafficking defective mutations.
Methods: Patient-specific iPSC-CMs models of KCNH2-G604S and KCNH2-N633S were generated from two unrelated patients diagnosed with severe LQT2 (QTc>580ms). Two control iPSC-CMs were analyzed. Both variants were also expressed heterologously in HEK293 cells. hERG protein expression profiles were tested using western blot and immunofluorescence before and after LUM (10µM) treatment. ArcLight- and ANEPPS voltage dye-based APD90 measurements were used to assess APD90 before and after LUM treatment.
Results: Both mutations were hERG trafficking defective in the patient iPSC-CMs and HEK293 cell systems. While LUM treatment failed to rescue their trafficking defect in the HEK293 cell system, LUM rescued completely the hERG trafficking defect for both mutations in the iPSC-CMs. Control iPSC-CM APD90 measurements were 417±20ms (1Hz) and 461±23 ms (0.5Hz). The APD90 of KCNH2-N633S iPSC-CMs (613±16ms, 1Hz and 564±29ms, 0.5Hz) where significantly shortened with LUM (476±21ms, 1 Hz and 501±11ms, 0.5Hz; p<0.05). However, LUM treatment of the KCNH2-G604S iPSC-CMs APD90 were not rescued in 1 Hz pacing (before LUM 597±25ms vs. after LUM 565±13ms, 1Hz, ANEPPS) and further prolonged (before LUM 637±28ms vs. after LUM 1088±85ms, 0.5Hz, Arclight), suggesting the rescue of dysfunctional hERG channels to the cell membrane.
Conclusion: While LUM is an effective hERG channel trafficking chaperone and may be a novel treatment for patients with LQT2, we urge caution. Without understanding the functionality of the potassium channel to be rescued, LUM therapy could be harmful to the patient. Efficacy studies using LQT2 variant-specific iPSC-CMs may be a useful pre-LUM treatment screening strategy.