University of Utah (“The U”) research reveals that an overactive defense response may lead to increased blood clotting, disease severity, and death from COVID-19. A team from the University of Utah Health and PEEL Therapeutics in collaboration with Cold Spring Harbor Laboratory and Weill Cornell Medicine have published these findings in the journal Blood. They have found that NETosis, a phenomenon in which infection-fighting cells emit a web-like substance to trap invading viruses, is actually part of an immune response that represents an intensified hyperactive response in patients with ventilators and those that have died from SARS-CoV-2. The conclusion here informs for the first time a possible method for lung injury in COVID-19 patients heretofore not identified as a treatment target. The researchers may have identified a naturally occurring protein that quiets this NET immune response in laboratory experiments and could represent a possible new treatment target. The intellectual property of The U, PEEL Therapeutics has secured an exclusive license and will seek to progress to clinical trials. That is an expensive endeavor, and therefore an Investor Watch story.
As patients afflicted with severe to critical COVID-19 become critically ill with respiratory distress, representing about 10% of the total COVID-19 population, the morbidity and mortality rate becomes high and the consequences severe. Loved ones are lost in the most tragic manner—with no family or friends to be there with them. The causes of lung damage in COVID-19 patients is consequently a subject of intense investigation and the University of Utah shares in their press release that increased blood clotting could lead to complications caused by the disease. The study’s first author and a critical care specialist at the University of Utah Health, Elizabeth Middleton, MD, reports, “This study tells us about a potential mechanism for lung injury in COVID-19 that had not previously been recognized as a possible target for treatment.”
In order to determine whether NETs could be responsible for complications seen in COVID-19, the multi-site team examined plasma from 33 patients, along with tracheal aspirates from the lungs. They found that NET activity correlated with disease severity.
In this investigation, the researchers also uncovered that a naturally occurring protein, originally found in umbilical cord blood, quiets this NET immune response in laboratory experiments. This discovery could open the door for new possible treatment ideas. The study was published on June 29, 2020 in Blood titled “Neutrophil Extracellular Traps (NETs) Continue to Immunothrombosis in COVID-19 Acute Respiratory Distress Syndrome.”
The team, including Middleton and other physician-scientist from the University of Utah Health as well as co-authors Christian Con Yost, MD, and Joshua Schiffman, MD, and colleagues, studied NETosis, a specific immune response associated with COVID-19 patients. They found that during the immune response, white blood cells actually release web-like Neutrophil Extracellular Traps (NETs) to capture and kill pathogens. This is supposed to of course be beneficial. As it turns out, Dr. Yost has studied NETs in the past and discovered that they can exacerbate at least some illnesses. For example, during an overwhelming infection, NETs can actually clog blood vessels and hence cause inflammatory tissue damage.
The team found that those patients that were either on life support and/or those who died from COVID-19 exhibited greater signs of NET activation that those patients who were not as ill or who ultimately recovered. That the NET immune response is even lower in healthy people and that it is associated with a biomarker for blood-oxygen levels reveals a growing importance of better understanding how to possibly treat this condition.
Finally, the team uncovered that plasma from sick patients triggers the NET response. They looked into experiments in the laboratory and found that plasma from COVID-19 patients stimulates while blood cells from health patients to “shoot out 50 times as many NETs as cells exposed to plasma from otherwise healthy adults.”
Support from Cold Spring Harbor Laboratory
Researchers at Cold Spring Harbor Laboratory supported this effort with lab research centering on the probe of deceased COVID-19 patients; they found that the blood vessels in the lungs of the deceased subjects were dotted with clumps of NET-producing cells and a critical type of blood cell for clotting, the platelets. University of Utah Health research have evidenced that platelets become hyperactive during the disease.
Neonatal NET Inhibitory Factor (nNIF)
The teams also uncovered that neonatal NET inhibitory Factor (nNIF), a small protein found in umbilical cord blood of newborn babies, quiets this hyperactive NET response in those white blood cells treated with COVID-19 patient plasma. This peptide could perhaps protect babies from harmful inflammation in early life, suggests PEEL Therapeutics CEO. The company is presently looking into this protein as a basis for a clinical treatment.
Hypothesis Moving Forward
Dr. Yost reports on an emerging hypothesis: COVID-19 disease severity and even mortality can possibly be determined by NET levels in the blood. This is critically important because as Dr. Yost conveyed in the University of Utah press release, health care providers need to understand how to identify which COVID-19 patients are in more danger of morbidity and mortality. Hence, moving forward, larger studies should be conducted to investigate if NETs could become a true COVID-19 severity level biomarker.
Funding & Support
· National Institutes of Health
· University of Utah’s 3i Initiative
· Fonds voor Wetenschappelijk Onderzoek Vlaanderen FWO
· Animal Cancer Foundation
· Soccer for Hope Foundation, Closer to Cure Foundation
· PEEL Therapeutics, Inc.
· William C. and Joyce C. O’Neill Charitable Trust
· the Linartz-Meier Family Foundation
· U.S. Department of Veterans Affairs
Business Dealings for Investor Watch
Note that these researchers are seeking to commercialize this knowledge. Dr. Yost with University of Utah authored a U.S. patent held by the University of Utah for the use of NET-inhibitory peptides. The University of Utah has extended an exclusive license to PEEL Therapeutics.
Study co-authors Abegglen and Lovino are consultants for and were awarded stock options in PEEL Therapeutics while both Schiffman and co-author Caulin are employed by, and were awarded stock options by PEEL Therapeutics. Thus, this University of Utah (and Technion-Israel Institute of Technology) spinoff PEEL Therapeutics, founded by Joshua Schiffman, seeks to leverage the patent and breakthrough in a commercial undertaking. The commercial opportunity: determine if the small protein that occurs in newborn infants to block inflammation from NETs could possibly help in the fight against COVID-19. The venture has been incubated by The U’s Center for Technology & Venture Commercialization.
PEEL Therapeutics & University of Utah Partnership
The two organizations are collaborating as it was staff from “The U” that discovered the natural NET inhibitors in the umbilical cord from newborn babies and is now preparing a new class of anti-inflammatory drug called Neutrophil Targeting Peptides (NTPs) to block NETs.
About PEEL Therapeutics
PEEL Therapeutics is a pre-clinical stage biotech operating to progress to clinical trials a new class of anti-inflammatory drug called Neutrophil Targeting Peptides (NTPs) to block NETs. The venture secured Adobe Co-founder John Warnock as well as Chicago Pacific Founders’ Mary Tolan on their board. Founded back in 2015 with a focus on cancer, the venture has secured $9.3 million.
Elizabeth Middleton, MD, critical care specialist, University of Utah Health
Mikala Egeblad, PhD, cancer researcher, Cold Spring Harbor Laboratory
Call to Action: Investigations are underway to assess if NETs and platelets actually increase the risk for blood clotting and other clinical manifestations of COVID-19. This research reveals the importance of considering investigations into NETs role in blood clotting in those with COVID-19. PEEL Therapeutics has been established to progress this breakthrough into the expensive domain of clinical trials. Hence, PEEL Therapeutics falls under TrialSite News’ “Investor Watch.”