Exploring disease-causing traits for drug repurposing in critically ill COVID-19 patients: A causal inference...

Area of Science:

• Immunology
• Genetics
• Pharmacology

Background:

• Effective treatments for critically ill COVID-19 patients are still needed, even with vaccine development.
• Genome-wide association studies (GWASs) can identify drug repurposing targets but often lack direct causal links to disease.
• Identifying disease-causing traits beyond immediate genetics is crucial for effective drug discovery.

Purpose of the Study:

• To develop and validate an alternative method for identifying drug repurposing targets for critical COVID-19.
• To investigate disease-causing traits associated with severe COVID-19 illness.
• To identify specific molecular targets and therapeutic agents for COVID-19 treatment.

Main Methods:

• Screened sixty blood cell types and biochemistries, plus body mass index, in critically ill COVID-19 cases and mild controls.
• Utilized a novel methodology focusing on disease-causing traits beyond direct genetic associations.
• Validated identified drug targets, CDK6 and janus kinase (JAK) inhibitors, using an ex vivo neutrophil extracellular trap (NET) formation assay.

Main Results:

• High neutrophil cell count was identified as a potential causal trait for critical COVID-19 illness.
• CDK6 and janus kinase (JAK) inhibitors were identified as promising therapeutic targets.
• The identified targets demonstrated efficacy in an ex vivo neutrophil extracellular trap (NET) formation assay, validating the methodology.

Conclusions:

• The study presents a powerful new methodology for drug target identification by analyzing large disease-causing trait datasets.
• High neutrophil count is implicated as a key trait in severe COVID-19, suggesting potential therapeutic avenues.
• CDK6 and JAK inhibitors show promise for repurposing as treatments for critical COVID-19, supported by experimental validation.