When a research project over 15 years in the making resulted in a drug that improved pulmonary function and oxygen delivery, researcher James D. Reynolds thought the drug could also help COVID-19 patients with severely compromised lung and heart function. Reynolds, Professor of Anesthesiology & Perioperative Medicine, was recently awarded a grant from the Harrington Discovery Institute’s (HDI) COVID-19 Rapid Response Initiative to answer that very question.
Reynolds and long-time collaborator, Jonathan Stamler, president of HDI, began their research at Duke University around 2005, and continued their work when they relocated to Case Western Reserve University’s School of Medicine and University Hospitals Cleveland Medical Center (UHCMC). They found that molecules called S-nitrosothiols (SNOs) decrease during infection, making breathing difficult and reducing oxygen delivery—actions which also appear to be a major cause of death in COVID-19 patients.
When gas exchange isn’t functioning properly in the lungs, oxygen can’t be absorbed by red blood cells that carry it to the rest of the body. Reynolds and Stamler discovered that the gas ethyl nitrite (ENO), the lead agent (drug) in their research, directly increases SNOs which are responsible for increasing oxygen delivery. The drug also alleviates lung inflammation, inhibits coronaviruses, and corrects SNO-based signals which can be disrupted by infection with SARS-CoV-2 (the official name for the virus that causes COVID-19). This unique combination of actions separates ENO from other therapeutic gases such as inhaled nitric oxide.
“Because our clinical work demonstrated the ability to improve oxygenation in healthy subjects, it might also be effective for the most severe COVID-19 on ventilators, whose lungs are in an oxygen-deprived state,” Reynolds stated. “Additionally, other investigators showed that SNOs can also have anti-inflammatory and antiviral activity. Blending ENO into oxygen supplying ventilators in very controlled doses could help patients in respiratory distress, as well as have potential synergistic benefit when administered with other drugs.”
The next step will be to secure FDA clearance for testing ENO to treat COVID-19 patients. Reynolds and his team have already initiated conversations with the FDA, developed the required toxicology data, and have successfully exposed subjects to ENO with no identified adverse effects. Additionally, good manufacturing practices (GMP) to develop a pharmaceutical-grade drug are in place, also important for FDA clearing.
In the short term, the team will conduct research on COVID-19 patients who are intubated on respiratory support. The longer-term goals will involve a three-stage drug development process:
- The first stage will consist of safety and initial efficacy testing, looking for a signal after acute exposure to see if patients’ oxygen parameters improve.
- The second stage will involve a randomized trial with longer exposure to ventilated patients, looking for differences in length of hospital stay, improved recovery rates and decreased mortality.
- In the third stage, treatment will begin earlier, before COVID-19 patients require ventilators.
“Our research wouldn’t be possible without this award from HDI, the strong institutional support provided by CWRU and UHCMC, and the direct participation of various UHCMC caregivers and critical care staff who are on the frontlines treating these patients. It’s a great example of team science,” Reynolds concluded.
About Harrington Discovery Institute
The Harrington Discovery Institute at University Hospitals in Cleveland, OH—part of The Harrington Project for Discovery & Development—aims to advance medicine and society by enabling our nation’s most inventive scientists to turn their discoveries into medicines that improve human health. The institute was created in 2012 with a $50 million founding gift from the Harrington family and instantiates the commitment they share with University Hospitals to a Vision for a ‘Better World’. For more information, visit: HarringtonDiscovery.org.