High throughput screens identify genotype-specific therapeutics for channelopathies

Genetic diseases such as ion-channelopathies substantially burden human health. Existing treatments are limited and not genotype specific. Here, we report a two-step high-throughput approach to rapidly identify drug candidates for repurposing as genotype-specific therapy. We first screened 1,680 medicines using a new thallium-flux trafficking assay against KV11.1 gene variants causing Long QT Syndrome (LQTS), an ion-channelopathy associated with fatal cardiac arrhythmias. We identify evacetrapib as a suitable drug candidate that improves membrane trafficking and activates channels. We then use deep mutational scanning to prospectively identify all KV11.1 missense variants in a LQTS hotspot region responsive to treatment with evacetrapib. Combining high-throughput drug screens with deep mutational scanning establishes a new paradigm for mutation-specific drug discovery translatable to personalized treatment of patients with rare genetic disorders.