The purpose of this COVID-19 research supplement is to critically evaluate if a calcitonin gene-related peptide (CGRP) receptor antagonist can mitigate both neuroinflammatory and hyper-immune responses to SARS-CoV-2 infection. In December 2019, the coronavirus disease (COVID-19) caused by severe acute respiratory syndrome CoV-2 (SARS-CoV-2) was identified. There are now over ~5.5 million confirmed cases worldwide (1.6 million US), and 345,000 deaths (~100,000 US). COVID-19 causes a respiratory illness like the flu with symptoms such as fever, cough, loss of smell, fatigue, sputum production, shortness of breath, sore throat, headache, chills, and nausea or vomiting. Approximately 80% of people have mild disease and recover. However, in those remaining 20%, COVID-19 is severe and there is evidence that progression to the most serious type of COVID-19 illness is related to a hyper-immune response (ie, cytokine storm). Currently, there are no effective vaccines or treatments available for COVID-19. In this supplement we will test the ability of CGRP-receptor antagonists to inhibit the neuroimmune consequences of SARS-CoV-2 infection, using temperature and nausea as an indicator of SARS-CoV2 infection, as we are doing in our parent grant to assess migraine nausea pain. A humanized mouse model has been developed for studying SARS-CoV2, where mice express the human angiotensin-converting enzyme 2 (hACE2), enabling us to model Covid-19 in the mouse. The FDA has recently approved Biohaven Pharmaceuticals to proceed to a phase 2 clinical trial of its CGRP-receptor antagonist (vazegepant; currently in phase 3 trials for migraine) to treat patients with severe COVID-19, suggesting that the neuroinflammatory reaction that is initiated by CGRP in response to SARS- CoV2 could be a therapeutic target for treating severe Covid-19, and that the non-invasive readouts of neuroinflammation that we are developing could be used to rapidly identify at risk patients. Our hypothesis is that mild to severe COVID-19 symptoms will occur in the transgenic hACE2 mouse that has been infected with SARS-CoV-2, and that a CGRP receptor antagonist will mitigate these symptoms.
The specific aims are to test the following hypotheses that transgenic mice and non-carrier littermates infected with SARS-CoV-2 will exhibit:
aim 1) mild severe symptoms based on viral load, and if these symptoms are less severe when treated with a CGRP-receptor antagonist;
and aim 2) reduced fever and nausea-like pain when treated with a CGRP- receptor antagonist. Information gained from these studies will provide a direct assessment of whether a CGRP-receptor antagonist can mitigate both mild and severe symptoms associated with SARS-CoV-2 infection. This proposal also impacts the development of robust preclinical in vivo assays of COVID-19 symptoms, paving the way to develop and test future therapeutics for COVID-19.
In December 2019, the coronavirus disease (COVID-19) was identified, and here are now over ~5.5 million confirmed cases worldwide (1.6 million US), and 345,000 deaths (~100,000 US). COVID-19 causes a respiratory illness like the flu with symptoms such as fever, cough, shortness of breath, sore throat, headache, chills, and nausea. Approximately 80% of people have mild disease and recover, yet in the remaining 20%, COVID-19 is severe and there is evidence that progression to the most serious type of COVID-19 illness is related to an increased immune response (ie, cytokine storm) often causing death. CGRP receptor blockers (currently used for migraine treatments) may keep the cytokine storm from developing. We will test this idea in mouse models that can be infected with the virus causing COVID19, and will measure fever, and a novel nausea-readout to determine if CGRP blockers can reduce the severity of COVID-19 symptoms.
| Jones, Sherri M; Vijayakumar, Sarath; Dow, Samantha A et al. (2018) Loss of ?-Calcitonin Gene-Related Peptide (?CGRP) Reduces Otolith Activation Timing Dynamics and Impairs Balance. Front Mol Neurosci 11:289 |
