Improving Existing Drugs for Long QT Syndrome type 3 (LQT3) by hiPSC Disease-in-Dish Model

This project used patient human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes to develop a safe and effective drug to treat a serious heart health condition (i.e., “disease in a dish”). In the US, an estimated 850,000 adults are hospitalized for arrhythmias every year. Arrhythmias are one of the top five causes of healthcare expenditures in the US: more than $40 billion annually is spent for diagnosis, treatment and rehabilitation. Most serious arrhythmias affect people older than 60 because older adults are more likely to have heart disease and other health problems that can lead to arrhythmias. Older adults also tend to be more sensitive to the side effects of medicines, some of which can cause arrhythmias. Some medicines used to treat arrhythmias can even cause arrhythmias as a side effect.  In the US, atrial fibrillation (a common type of arrhythmia) affects millions of people and the number is rising. We developed a novel drug candidate for a human genetic heart disorder characterized by long delay (long Q-T interval) between heart beats caused by mutations in the Na⁺ channel α subunit. We used patient-derived hiPSC-cardiomyocytes to develop a safe drug candidate that retained efficacy against a "leaky" Na⁺-channel yet minimized off-target effects against the K⁺ hERG channel that can be responsible for currently used drug’s pro-arrhythmic effect.  Because this problem occurs in patients with the common KCHN2 variant, K897T (~33% of the white population), removing off-target liability addresses a serious unmet clinical need. Drug development has resulted in a safer, more selective and potent drug candidate.  We successfully accomplished our goal of developing a drug candidate and initiating IND-enabling studies. Successful completion of this work has provided much needed advances in cardiovascular health technology and improvement in health care and an improved heart drug candidate.