# High-throughput screens identify genotype-specific therapeutics for channelopathies

## TL;DR

A new method identifies genotype-specific drugs for genetic diseases like long QT syndrome, offering hope for personalized treatments.

## Contribution

A two-step high-throughput approach combining drug screening and deep mutational scanning for mutation-specific drug discovery.

## Key findings

- Evacetrapib improves membrane trafficking and activates channels in Kv11.1 gene variants causing long QT syndrome.
- Deep mutational scanning identified all Kv11.1 missense variants responsive to evacetrapib treatment.
- The method establishes a paradigm for personalized treatment of rare genetic disorders.

## 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.

Using two-step high-throughput approach for drug repurposing, we identified evacetrapib as a potential treatment for Long QT Syndrome, paving the way for personalized therapies for genetic disorders.