This article is part of Harvard Medical School’s continuing coverage of medicine, biomedical research, medical education and policy related to the SARS-CoV-2 pandemic and the disease COVID-19.
Harvard Medical School researchers at Boston Children’s Hospital and Brigham and Women’s Hospital will soon begin testing an existing drug, dornase alfa, in patients with severe COVID-19 pneumonia and respiratory failure.
The randomized, controlled clinical trial aims to enroll 60 adults and children over age 3 who require mechanical ventilation.
Dornase alfa, also known as DNase 1 or Pulmozyme, is FDA-approved for cystic fibrosis to break up thick mucus secretions and prevent lung infections. The drug may also break up neutrophil extracellular traps, or NETs, which scientists believe contribute to lung inflammation.
“We hope this drug, which is known to be safe, will help reduce the inflammation that contributes to worsening respiratory distress in COVID-19,” said the study's lead investigator, Benjamin Raby, the Leila and Irving Perlmutter Professor of Pediatrics at HMS and chief of pulmonary medicine at Boston Children’s.
Off the ventilator?
The 18-month study will randomize patients to dornase alfa or placebo (a saline solution) soon after placement on a ventilator.
Patients will receive twice-daily nebulized treatments through the ventilator tubing.
Raby and colleagues will monitor them for up to 28 days, or until they come off the ventilator, whichever is sooner. Neither the researchers nor the patients or their families will know which treatment is being given.
The main outcome being tracked is how many patients in each group are alive and ventilator-free at 28 days. Other measures include airway resistance to breathing, lung compliance (the lungs’ ability to stretch and expand), blood oxygenation and length of stay in the ICU and hospital.
Dornase alfa is known to soften thick mucus, which some patients with COVID-19 pneumonia produce in large amounts. That could make it easier to deliver oxygen through the ventilator.
The drug may have an additional benefit: breaking up NETs.
NETs are webs of DNA and toxic protein that neutrophils—first-responder cells in the immune system—spew out to entrap microbes. NETs have a down side: They can produce dangerous blood clots in the lung, such as those that form in COVID-19 patients. These clots can contribute to lung inflammation and injury.
Denisa Wagner, HMS professor of pediatrics at Boston Children’s, helped initiate the new trial. Her lab has been studying NETs for more than a decade and has implicated NETs in unwanted clot formation and fibrosis (thickening and scarring of tissue).
Wagner’s findings, and those of others, suggest that dornase alfa could benefit COVID-19 patients with severe lung injury.
“Preclinical studies have found that DNase 1 improved outcome in lung injury models and in thrombotic (clotting) models,” Wagner said. “These models mimic events that occur frequently in COVID-19, such as deep vein thrombosis, stroke and microvascular thrombosis.”
While the new study focuses on the lung, scientists hypothesize that NETs contribute to excess clotting seen elsewhere in the body in COVID-19.
Genentech is providing the drug as well as supplementary financial support. The Massachusetts Consortium on Pathogen Readiness is also supporting the trial.
Other study principals include Rebecca Baron and Laura Fredenburgh of HMS and Brigham and Women’s and Meera Subramaniam and Gregory Sawicki of HMS and Boston Children’s.
Adapted from a post on Discoveries, the Boston Children's research and clinical innovation portal.