The Potential Alzheimer’s Disease Drug, GM‐CSF, Enhances the Anti‐Viral Immune Response and Reduces Mortality in a Mouse Model of COVID‐19

Abstract

AbstractBackgroundCOVID‐19 results in increased expression of inflammatory cytokines and Alzheimer’s disease (AD) biomarkers of neuronal damage, but inflammation‐targeting clinical trials have yielded poor to mixed results. Our studies of other disorders with an inflammatory component, including AD, chemobrain, Down syndrome, normal aging, and West Nile Virus infection, showed that treatment with the ‘pro‐inflammatory’ cytokine granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) in humans or mouse models alleviated clinical, behavioral, and pathological features. Most recently, we completed a Phase 2 clinical trial (NCT01409915) using sargramostim/Leukine (rhuGM‐CSF) in mild‐to‐moderate AD participants, which showed that three weeks of sargramostim treatment improved MMSE scores and improved ATN blood biomarkers of AD pathology (Potter et al., 2021). Therefore, we proposed that human GM‐CSF may be repurposed to promote both the innate and adaptive immune responses in COVID‐19 patients to reduce viral load and mortality.MethodWe investigated GM‐CSF’s effects in eight‐week old male and female human ACE2 (hACE2) transgenic mice infected intranasally with 104 PFU of SARS‐CoV‐2 virus and followed them for 14 days. Mice received daily IP injections of either recombinant murine GM‐CSF or saline. Viral titers, anti‐spike protein antibody levels, and mortality were assessed.ResultsIntranasal inoculation of hACE2 transgenic mice with 104 PFU SARS‐CoV2 virus resulted in high viral titers in lungs and brains and over 85% mortality. GM‐CSF treatment beginning one day post‐infection increased anti‐spike protein antibody titers, lowered mean lung viral titers proportionately (p = 0.0020), and increased the odds of long‐term survival by up to 5.8‐fold (p = 0.0358), compared to saline.Conclusion GM‐CSF represents a new approach to the treatment of COVID‐19 by recruiting inflammation and the immune system to attack SARS‐CoV‐2 infection and promote survival. GM‐CSF is likely to have a significant advantage over current approaches to the treatment of COVID‐19, including anti‐virus monoclonal antibodies, drugs designed to inhibit viral replication, and immunosuppressants, because, unlike short‐term antivirals, it activates the endogenous immune system, with likely long‐term increases in immune memory required for protection against re‐infection, Based on its mode of action as a natural stimulator of the immune response, GM‐CSF should be effective against all current and future SARS‐CoV‐2 variants.