High-throughput screens identify genotype-specific therapeutics for channelopathies

Area of Science:

• Genetics
• Pharmacology
• Cardiology

Background:

• Genetic diseases, particularly ion channelopathies like long QT syndrome (LQTS), pose significant health challenges.
• Current treatments for LQTS lack genotype specificity, limiting their effectiveness.
• There is a critical need for novel therapeutic strategies that target specific genetic mutations.

Purpose of the Study:

• To establish a high-throughput screening approach for identifying drug candidates for repurposing as genotype-specific therapies.
• To discover drugs that can address Kv11.1 gene variants responsible for LQTS.
• To develop a personalized treatment strategy for rare genetic disorders.

Main Methods:

• A two-step high-throughput screening process was employed.
• 1,680 existing medicines were screened using a thallium-flux trafficking assay against Kv11.1 variants.
• Deep mutational scanning was utilized to identify all responsive Kv11.1 missense variants in a specific region.

Main Results:

• Evacetrapib was identified as a drug candidate that enhances membrane trafficking and activates Kv11.1 channels.
• The study successfully identified specific Kv11.1 variants in an LQTS hotspot responsive to evacetrapib treatment.
• The combined approach demonstrated the potential for mutation-specific drug discovery.

Conclusions:

• The developed two-step screening method enables rapid identification of genotype-specific drug candidates.
• Evacetrapib shows promise for treating LQTS caused by specific Kv11.1 variants.
• This paradigm facilitates personalized medicine for rare genetic disorders by enabling mutation-specific drug discovery.