An Experimental Medicine Approach to Understand the Mechanisms Underpinning the Post-Acute Sequelae of COVID-19

Post-Acute Sequelae of COVID-19 (PASC) presents as a heterogenous collection of symptoms including unremitting fatigue, post-exertional malaise and cognitive and autonomic impairment, and impacts up to 65 million people globally. There is an urgent need to understand the mechanistic basis for these symptoms to identify therapeutic targets and prognostic biomarkers. We were among the first in the world to describe the immune and neurological dysregulation that persist in PASC patients following SARS-CoV-2 infection. Since then, a growing number of observational studies have identified a wide range of immunological and neurological changes that are associated with PASC, but we are still no closer to knowing which of these are the causal mechanisms driving PASC. We believe that the results of a recent clinical trial provide an exciting new opportunity to uncover the causal mechanisms that drive PASC. This trial showed that metformin, a safe and widely administered drug usually given to people with Type II diabetes, led to 40% reduced risk of developing PASC. Why metformin has these effects is unknown.

Uncovering this would provide strong evidence as to which mechanistic pathways and biomarkers are aetiological (causal) of PASC and which are bystander correlates. Here, we propose an innovative experimental medicine study where we will collect blood and stool samples from individuals living with PASC before and after treatment with metformin and apply a highly multidisciplinary approach to comprehensively assess the changes to the immune system, microbiota, and peripheral and central nervous system that are induced in PASC patients that respond to metformin, compared to those that don’t. Our proposal will generate sorely needed new knowledge of the causal drivers of PASC to support the development of novel diagnostic tools and therapies for individuals living with this condition.