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

Background COVID‐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. Method We 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. Results Intranasal 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.

Neurology of Acute Viral Infections.

As specialists in acute neurology, neurohospitalists are often called upon to diagnose and manage acute viral infections affecting the nervous system. In this broad review covering the neurology of several acute viral infections, our aim is to provide key diagnostic and therapeutic pearls of practical use to the busy neurohospitalist. We will review acute presentations, diagnosis, and treatment of human herpesviruses, arboviruses, enteroviruses, and some vaccine-preventable viruses. The neurological effects of coronaviruses, including COVID-19, are not covered in this review.

Neurology and the COVID-19 Pandemic: Gathering Data for an Informed Response.

PURPOSE OF REVIEW: The current coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of the greatest medical crises faced by our current generation of health care providers. Although much remains to be learned about the pathophysiology of SARS-CoV-2, there is both historical precedent from other coronaviruses and a growing number of case reports and series that point to neurologic consequences of COVID-19. RECENT FINDINGS: Olfactory/taste disturbances and increased risk of strokes and encephalopathies have emerged as potential consequences of COVID-19 infection. Evidence regarding whether these sequelae result indirectly from systemic infection or directly from neuroinvasion by SARS-CoV-2 is emerging. SUMMARY: This review summarizes the current understanding of SARS-CoV-2 placed in context with our knowledge of other human coronaviruses. Evidence and data regarding neurologic sequelae of COVID-19 and the neuroinvasive potential of human coronaviruses are provided along with a summary of patient registries of interest to the Neurology community.

Recruiting the innate immune system with GM-CSF to fight viral diseases, including West Nile Virus encephalitis and COVID-19.

As the coronavirus disease 2019 (COVID-19) pandemic grows throughout the world, it is imperative that all approaches to ameliorating its effects be investigated, including repurposing drugs that show promise in other diseases. We have been investigating an approach to multiple disorders that involves recruiting the innate immune system to aid the body's healing and regenerative mechanism(s). In the case of West Nile Virus encephalitis and potentially COVID-19, the proposed intervention to stimulate the innate immune system may give the adaptive immune response the necessary time to develop, finish clearing the virus, and provide future immunity. Furthermore, we have found that GM-CSF-induced recruitment of the innate immune system is also able to reverse brain pathology, neuroinflammation and cognitive deficits in mouse models of Alzheimer's disease and Down syndrome, as well as improving cognition in normal aging and in human patients with cognitive deficits due to chemotherapy, both of which exhibit neuroinflammation. Others have shown that GM-CSF is an effective treatment for both bacterial and viral pneumonias, and their associated inflammation, in animals and that it has successfully treated pneumonia-associated Acute Respiratory Distress Syndrome in humans. These and other data strongly suggest that GM-CSF may be an effective treatment for many viral infections, including COVID-19.

COVID-19: A Global Threat to the Nervous System.

In less than 6 months, the severe acute respiratory syndrome-coronavirus type 2 (SARS-CoV-2) has spread worldwide infecting nearly 6 million people and killing over 350,000. Initially thought to be restricted to the respiratory system, we now understand that coronavirus disease 2019 (COVID-19) also involves multiple other organs, including the central and peripheral nervous system. The number of recognized neurologic manifestations of SARS-CoV-2 infection is rapidly accumulating. These may result from a variety of mechanisms, including virus-induced hyperinflammatory and hypercoagulable states, direct virus infection of the central nervous system (CNS), and postinfectious immune mediated processes. Example of COVID-19 CNS disease include encephalopathy, encephalitis, acute disseminated encephalomyelitis, meningitis, ischemic and hemorrhagic stroke, venous sinus thrombosis, and endothelialitis. In the peripheral nervous system, COVID-19 is associated with dysfunction of smell and taste, muscle injury, the Guillain-Barre syndrome, and its variants. Due to its worldwide distribution and multifactorial pathogenic mechanisms, COVID-19 poses a global threat to the entire nervous system. Although our understanding of SARS-CoV-2 neuropathogenesis is still incomplete and our knowledge is evolving rapidly, we hope that this review will provide a useful framework and help neurologists in understanding the many neurologic facets of COVID-19. ANN NEUROL 2020;88:1-11 ANN NEUROL 2020;88:1-11.