Improving mutant KV11.1 trafficking to treat Long QT Syndrome

Long QT Syndrome (LQTS) occurs due to slowed cardiac repolarization, which is reflected as long QT intervals on patient electrocardiograms. This prolongation increase the risk of fatal cardiac arrhythmias. The voltage-gated potassium ion channel, KV11.1, comprises 25-40% of LQTS cases. Around 90% of loss-of- function KV11.1 variants cause reduced intracellular transport (trafficking) of KV11.1 protein, reducing its cell surface expression and causing LQTS. Currently, there are no clinically approved drugs that treat this mechanism. My high-throughput drug screens identified evacetrapib as a drug candidate that improves KV11.1 trafficking and activates the channels. For this project, I aim to 1) test evacetrapib for drug repurposing in trafficking-deficient KV11.1 variants and 2) identify targetable KV11.1 protein interactions that could improve trafficking and function. Aim 1 uses high throughput variant screening and human induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) to assess KV11.1 variant trafficking and function. In collaboration with Brett Kroncke, this proposal uses published multiplexed assays of variant effect (MAVE) to generate more than 23,000 KV11.1 variants and identify variant-specific trafficking response to evacetrapib. Evacetrapib failed phase III clinical trials for high cholesterol, but patients tolerated the drug well, suggesting it could be repurposed to treat Long QT Syndrome. Thus, data from the MAVE will inform testing in translational hiPSC-CM models. Gene-edited or patient-derived HiPSC-CMs with responsive KV11.1 variants will be used to further confirm evacetrapib’s efficacy and facilitate the translation of the findings into clinical practice. Aim 2 explores KV11.1-protein interaction networks using established affinity-purification coupled with mass spectrometry protocols and high-throughput siRNA screening. This will identify KV11.1 interacting proteins and mechanisms that regulate KV11.1 trafficking. Dr. Egly will receive hands-on training in proteomics (instrumentation and analysis), which complements prior learning from courses and workshops. Dr. Christian Egly’s career goal is to establish an independent research lab focused on ion channel trafficking and finding new treatments for cardiac arrhythmias. The training plan highlights key areas for Dr. Egly’s growth including research independence in hiPSC-CMs (Aim 1) and proteomics (Aim 2), professional development, faculty development, and courses/learning of statistical analysis and bioinformatics. Mentors, Björn Knollmann, MD, Ph.D., and Lars Plate, Ph.D., have excellent track records in training students, fellows and early career investigators. Advisor Dan Roden, MD, offers decades of experience in cardiac electrophysiology and arrhythmia research and has trained multiple K awardees. Dr. Yaomin Xu provides biostatistical support to the project. Lastly, Vanderbilt University is an excellent environment with top-notch research facilities and investigators that will support Dr. Egly’s development towards independence. Project Number: 1K08HL177342-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Christian Egly | Institution: VANDERBILT UNIVERSITY MEDICAL CENTER, NASHVILLE, TN | Award Amount: $131,571 | Activity Code: K08 | Study Section: NHLBI Mentored Clinical and Basic Science Study Section[MCBS (MA)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K08HL17734201A1