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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.
Document Type
Article
Publication Date
11-24-2025
Digital Object Identifier (DOI)
10.1172/jci.insight.191697
Archival?
Archival
Repository Citation
Egly, Christian L.; Shen, Alex; Do, Tri Q.; Cabiya, Carlos Tellet; Ritschel, Paxton A.; Woo, Suah; Ku, Matthew; Delisle, Brian P.; Kroncke, Brett M.; and Knollmann, Björn C., "High-throughput screens identify genotype-specific therapeutics for channelopathies" (2025). Physiology Faculty Publications. 231.
https://uknowledge.uky.edu/physiology_facpub/231
Notes/Citation Information
Publisher Copyright: © 2025, Egly et al.