Abstract
Genetic diseases such as ion channelopathies substantially burden human health. Existing treatments are limited and not genotype specific. Here, we report a 2-step high-throughput approach to rapidly identify drug candidates for repurposing as genotype-specific therapy. We first screened 1,680 medicines using a thallium-flux trafficking assay against Kv11.1 gene variants causing long QT syndrome (LQTS), an ion channelopathy associated with fatal cardiac arrhythmia. We identified evacetrapib as a suitable drug candidate that improves membrane trafficking and activates channels. We then used deep mutational scanning to prospectively identify all Kv11.1 missense variants in an LQTS hotspot region responsive to treatment with evacetrapib. Combining high-throughput drug screens with deep mutational scanning establishes a paradigm for mutation-specific drug discovery translatable to personalized treatment of carriers with rare genetic disorders.
| Original language | English |
|---|---|
| Article number | e191697 |
| Pages (from-to) | 1-15 |
| Number of pages | 15 |
| Journal | JCI insight |
| Volume | 11 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jan 23 2026 |
Bibliographical note
Publisher Copyright:© 2025, Egly et al.
Funding
This work is the result of NIH funding, in whole or in part, and is subject to the NIH Public Access Policy. Through acceptance of this federal funding, the NIH has been given a right to make the work publicly available in PubMed Central. • NIH grant R35HL144980 (to BCK) • NIH grants R01HL164675 and R01HL160863 (to BMK). • NIH grant T32GM007569 (to BCK and CLE). • NIH grant K08HL177342 (to CLE). • Saving Tiny Hearts grant GR018566 (to BCK and CLE). • Vanderbilt Faculty Research Scholars grants GR018830 and GR021063 (to CLE). • American Heart Association predoctoral fellowship 24PRE1243081 (to TQD). • Leducq Foundation grant 18CVD05 (to BCK). We thank the Vanderbilt University High Throughput Screening facility and Corbin Whitwell for compound management for the screens. We would also like to thank the Vanderbilt University Medical Center’s Flow Cytometry Resource Core for running the FACS. We would also like to thank the Vanderbilt Technologies for Advanced Genomics for Illumina sequencing and bioinformatics. NIH grant R35HL144980 (to BCK) NIH grants R01HL164675 and R01HL160863 (to BMK). NIH grant T32GM007569 (to BCK and CLE). NIH grant K08HL177342 (to CLE). Saving Tiny Hearts grant GR018566 (to BCK and CLE). Vanderbilt Faculty Research Scholars grants GR018830 and GR021063 (to CLE). American Heart Association predoctoral fellowship 24PRE1243081 (to TQD). Leducq Foundation grant 18CVD05 (to BCK).
| Funders | Funder number |
|---|---|
| Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center | |
| National Research Service Award predoctoral fellowship | |
| Saving Tiny Hearts Society | GR021063, GR018566, GR018830 |
| National Institutes of Health (NIH) | R01HL164675, R35HL144980, T32GM007569, R01HL160863, K08HL177342 |
| Fondation Leducq | 18CVD05 |
| American the American Heart Association | 24PRE1243081 |
UN SDGs
This output contributes to the following UN Sustainable Development Goals (SDGs)
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SDG 3 Good Health and Well-being
ASJC Scopus subject areas
- General Medicine
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