Medical personnel treating severe cases of COVID-19 focus much of their effort on keeping their patients alive until the body’s own defenses can rally, allowing them breathe on their own.
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Acute respiratory distress syndrome, known as ARDS, is a life-threatening condition in which fluid leaks into the lungs. Common in coronavirus patients, particularly older ones, it can lead to respiratory failure and death.
A ventilator is the main option currently available for treating patients with ARDS, in the hope that the mechanical aid to the lungs will enable them to survive. But in at least 50 percent of cases, and by some assessment as many as 70 percent, COVID-19 patients on ventilators never recover.
Four years ago, Prof. Josué Sznitman and his team from the Technion – Israel Institute of Technology in Haifa started developing a treatment for a condition similar to ARDS that can affect preterm infants whose immature lungs lack pulmonary surfactant, the liquid that coats the surface of alveoli in the lungs.
“For 30 years now we know that injecting liquid surfactant directly into the neonates’ lungs greatly helps the lungs function normally,” Sznitman says, adding that the method has a success rate of 98 percent in the infants’ saving the lives.
The problem is that the delivery method has been highly ineffective in adults because of differences in lung size. In larger lungs, liquid instillations quickly drain into pools, drowning some lung regions and leaving others entirely untreated.
The simple, elegant solution being developed in Sznitman’s laboratory is to turn the liquid surfactant into a foam. “Foam has more volume” than liquid, he explains, “and is less affected by gravity, so it can spread in a uniform manner through the lungs and restore the ‘facelift’ to the epithelial cells that they need to function properly,” he says.
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The invention, known as Liquid Foam Therapy, or LIFT, has been tested successfully on rats, which recovered to a healthy state within 15 to 30 minutes, with no adverse events. As rat lungs are too small to demonstrate improved distribution that is critically necessary in adult lungs, the team used ex vivo experiments in adult-sized pig lungs to show how LIFT spreads homogeneously compared with liquid administration.
Next month the laboratory hopes to begin preclinical tests in live pigs. If they succeed, Sznitman hopes to begin the first clinical trials of the therapy in humans this fall, to accelerate the development of a treatment.
“If the technique proves itself, it could also be used to administer drugs and other treatments directly into the lungs, such as stem cells that could help damaged lungs recover,” he says.
The research has support from the European Union and Israel’s Science, Technology and Space Ministry.
Another therapeutic approach to preventing the harsh ramifications of ARDS is now being studied in the laboratory of Prof. Naftali Kaminski, Boehringer-Ingelheim Endowed Professor of Internal Medicine and Chief of Pulmonary, Critical Care and Sleep Medicine, at Yale School of Medicine, and an expert on pulmonary medicine. Kaminski began his research several years ago, but has assumed far greater importance with the outbreak of the coronavirus pandemic.
"Three or four years ago we discovered that the thyroid hormone helps to protect the lining of the lung," Kaminski says. The thyroid hormone has large range of functions in the body and has been studied extensively for decades. This hormone plays an important role in cellular metabolism and affects the cells' ability to withstand crisis situations. "We discovered its potential for protecting lung cells quite by chance," Kaminski adds.
In the framework of his research, Kaminski is investigating pulmonary fibrosis, and in the past two years his team has examined the hormone's effect on the lungs' ability to recover from damage they sustained. Explaining the mechanism behind the hormone's activity, Kaminski said: "In general, the hormone improves the work of the mitochondria, 'the cells' power station' and causes the cells to create fewer toxic substances during metabolic activity. As a result, in crisis conditions the cells respond better and are harmed less."
However, the hormone's other functions, aside from improving cellular metabolism, pose a problem. "The hormone has two receptors – one binds to lung and liver cells and improves their functioning, and the other attaches to cells in the heart, muscles and digestive system," Kaminski explaines. For that reason, although a high concentration of the thyroid hormone can help protect the lungs, at the same time it is likely to cause problems in the muscles, the digestive system and other organs, as well as lead to arrhythmia.
"That's why we looked for molecules similar to the thyroid hormone, which are also safe for the heart and the digestive system," the Yale researcher says. During their search, Kaminski and his team stumbled upon a medication with a mechanism similar to that of the thyroid hormone. It was developed decades ago for treating cholesterol and neurological diseases, but was never put to use.
"The company that developed the medication was unable to raise the large sums of money required for long-term experiments to prove it was safe to use for treating chronic diseases," Kaminski explains. But the clinical study of the drug, which is called sobetirome, was discontinued only after its developers had demonstrated that it was safe for use for 28 days - longer than the time needed to treat coronavirus patients.
"We tested the effectiveness of the drug in mice and showed that it prevents damage to the cellular lining of the lungs," Kaminski says.
To prevent serious damage to the lung tissue later on, as well as other life-threatening situations, sobetirome can be administrated to coronavirus patients at the early stages of the disease – when they are suffering from mild symptoms and before the condition of some deteriorates and they start showing symptoms of ARDS.
"We're planning to embark soon on two experiments to be conducted on 260 patients who are hospitalized in moderate condition in the United States and Greece, designated to test whether the drug improves their chances of survival," Kaminski says. "We have obtained the drug, most of the required funding, and we hope to receive an answer from the U.S. Food and Drug Administration in the coming days," he adds, referring to an experiment conducted in cooperation with Prof. Argyrios Tzouvelekis, who was also involved in the original discovery.
Furthermore, the thyroid gland hormone increases the secretion of surfactant (the liquid that coats the surface of the lung alveoli) and the absorption of liquids in the lungs. "So it's possible that our drug and the foam being developed by Dr. Sznitman will have a complementary effect," Prof. Kaminski suggests.
Another possible advantage of sobetirome is its potential for preventing long-term damage caused to coronavirus patients. Even now there is evidence that patients who recover from the virus suffer from a significant decline in pulmonary function. "We believe that the drug could also help to reduce the long-term damage," explains Kaminski.
"We're now working on raising funds for a long-term aspect of the research." Kaminski is referring to a study that will conduct a follow-up of several of the subjects after two months or even a year from the moment of recovery, in order to test whether the drug is of real value in preventing prolonged damage.