Fetuses don’t scar. That insight — and its implications for wound healing in adults — led fetal and pediatric surgeon Kenneth Liechty, MD, and his research team deep into an investigation of the inflammatory response. The result: an ingenious two-pronged treatment that could potentially apply to any disease process hinging on inflammation, including acute respiratory distress syndrome, the leading cause of death in COVID-19.
What is ARDS and what does it have to do with fetal healing?
Acute respiratory distress syndrome, or ARDS, has devastating consequences. A massive inflammatory response to injury or infection floods the alveolar sacs with fluid. Tissues scar and fibrose. Mechanical ventilation can keep patients alive until the response subsides, but there’s no treatment.
Mortality approaches 50%. Even when patients survive, quality of life is significantly impacted.
“The fetus is unique, in that it’s able to regenerate a number of organs following injury, and it heals with minimal inflammation and oxidative stress,” says Dr. Liechty. “That’s a key pathology feature in a lot of disease processes, including ARDS.
“So the question was,” he continues, “how to fetalize the adult.”
The two prongs of inflammation
When injury occurs, the body’s first priority is to kill pathogens and close the wound. Immune cells crowd to the site and crank out pro-inflammatory proteins.
“Messenger RNA are the biggest regulators of pro-inflammatory gene expression,” says Dr. Leichty, “so we developed a strategy to target them.”
That strategy was a microRNA known as miR146a, a regulator of immune function that’s recently played a role in studies ranging from cancer to cystic fibrosis. It binds and neutralizes messenger RNA before it can reach the ribosome to produce proteins, interrupting the inflammatory pathway.
The problem was that it didn’t treat the other arm of inflammation: reactive oxygen species, volatile compounds that mangle the big, fragile molecules of life. Dr. Liechty’s team had a treatment for that, too: a nanoparticle called cerium oxide, which could bind and neutralize reactive oxygen species — but without gene regulation, the immune system would just crank out more.
The key was to combine the two.
Kenneth Liechty, MD
Director, Pediatric Surgery, Basic and Translational Research Co-Director
Colorado Fetal Care Center
Sandy Wolf Chair in Maternal Fetal Surgery
Children’s Hospital Colorado
Pediatric Surgery University of Colorado School of Medicine
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Cerium oxide and miR146a: a winning conjugation
The combination, which the team called “the conjugate,” proved an elegant solution: cerium oxide not only proved effective at shutting down oxidative stress, but was also a good delivery vehicle for miR146a, which downregulated the genetic pathway.
The team’s first area of study was diabetic wounds, which can become so inflamed they can’t heal. Applied to an animal model, the conjugate effectively corrected the rate of diabetic healing to normal. The team was already looking at ARDS when the pandemic came along. When that happened, the Food and Drug Administration accelerated the development of treatments for severe COVID-19, and Dr. Liechty’s team submitted an investigational new drug application. It got fast-tracked.
Using dosage guidelines they developed for diabetic wounds, the team delivered the conjugate in liquid form, via whole lung lavage, to two different animal models of ARDS: one induced by the chemotherapy bleomycin, the other induced by an endotoxin found on the outer membrane of gram-negative bacteria. Both models provoke brisk and immediate inflammation.
Given immediately after injury, the treatment was preventative: There was no lasting injury. Even given 4 hours later, 3 days later, 7 days later, it worked, even improving lung function.
“It makes the lungs basically normal,” says Dr. Liechty, “whereas if not treated, the lungs would scar and fibrose.”
True in any tissue
Dr. Liechty’s team is now studying the conjugate in an animal model infected with live pneumonia bacteria and expects to know more on that next year. Meanwhile, they’re beginning to apply the treatment to inflammatory bowel disease.
The potential indications go on. And with $2.2. million in funding from the National Institutes of Health, the team is well positioned to keep going. A $250,000 grant from the state of Colorado is currently helping set up manufacturing, which is slated to occur at the Gates Biomanufacturing Facility, a short walk from Children’s Hospital Colorado on the Anschutz Medical Campus.
“Any time you have a tissue injury, you have this inflammatory, proliferative, remodeling response,” Dr. Liechty. “That holds true in any tissue. If you can alter that response, you can fetalize the environment and promote regeneration instead of scarring. That’s what we’re doing.”