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University of Maryland School of Medicine (UMSOM) researchers, along with their colleagues, engineered a new molecule that appears promising as an effective antidote for carbon monoxide poisoning with fewer side effects than other molecules currently being tested, according to a new study in the journal PNAS.

Carbon monoxide poisoning accounts for 50,000 emergency room visits in the U.S. each year and causes about 1,500 deaths. These deaths may occur when carbon monoxide released from combustion builds up in an enclosed space, which can result from ventilation failures in indoor natural gas burning equipment, or running gasoline generators or automobiles indoors or in a closed garage. Carbon monoxide poisoning is also associated with most fires from smoke inhalation.

Currently, the only treatments for carbon monoxide poisoning are oxygen-based therapies, which help the body eliminate the toxic gas. However, even with treatment, nearly half of survivors suffer long-term heart and brain damage. This has created an urgent need for faster, more effective therapies.

In the new study, the research team developed a new engineered protein-based therapy called RcoM-HBD-CCC, which acts like a sponge to soak up carbon monoxide from the blood. Beginning with RcoM (short for "regulator of metabolism")—a natural protein the bacterium Paraburkholderia xenovorans uses to sense minute levels of carbon monoxide—the researchers engineered a version that is highly selective: It grabs carbon monoxide without interfering with oxygen or other important molecules in the body.

In tests on mice, the new therapy worked quickly to remove carbon monoxide from red blood cells and was safely flushed out of the body through urine. "Unlike other protein-based treatments, we found the compound caused only minimal changes in blood pressure, which was an exciting finding and raised the potential for this new molecule to have clinical applications," said study corresponding author Mark T. Gladwin.

"This has the potential to become a rapid, intravenous antidote for carbon monoxide that could be given in the emergency department or even in the field by first-responders."

How carbon monoxide kills

In healthy bodies, oxygen inhaled from the air binds to the protein hemoglobin on the surface of red blood cells, which then ferry the oxygen to all the tissues of the body. Inhaled poisonous carbon monoxide gas, however, competes with oxygen for hemoglobin. It enters the bloodstream and binds to hemoglobin with a 200 to 400-fold greater affinity than oxygen. That means carbon monoxide hogs most of the hemoglobin seats, so not enough oxygen molecules can get a ride to the tissues that need them.

Currently, the only available treatments for carbon monoxide poisoning involve giving 100% pure oxygen, sometimes under pressure in a hyperbaric chamber.

All too often, patients are not transported, diagnosed, and treated in time to reverse the effects of carbon monoxide poisoning, which can cause lasting cardiac and neurological injuries or even death.

"This molecule could be a game-changer because it can directly and rapidly remove carbon monoxide from the body with such a low risk of off-target side effects," said Jason J. Rose, another one of the study's researchers. "Given the promising results, we also see the potential for RcoM-HBD-CCC use in other areas, like as a blood substitute in severe anemia or hemorrhagic shock."

Bloodstream scavengers

The research team focused on engineering carbon monoxide "scavengers," which are proteins structurally similar to hemoglobin, known as hemoproteins, but exhibiting even greater binding affinity—stickiness—for carbon monoxide, and less affinity for binding oxygen.

Infused in the bloodstream, scavenger hemoproteins like RcoM-HBD-CCC rapidly bind to carbon monoxide molecules, reducing the time it takes to clear half of the carbon monoxide in the blood to less than a minute, compared to more than an hour with pure oxygen therapy and five hours without any treatment. When carbon monoxide is cleared, this frees hemoglobin on red blood cells to begin carrying oxygen once again.

But many hemoproteins also share some affinity for binding oxygen, and can therefore also scavenge nitric oxide, a molecule important in regulating blood pressure. Infusions of hemoproteins or hemoglobin can reduce the levels of nitric oxide in the blood, leading to tightened blood vessels and a rapid rise in blood pressure.

In this latest study, the researchers were surprised to find that RcoM-HBD-CCC did not result in an increase in blood pressure regardless of whether carbon monoxide was present in the blood. They theorize that while RcoM-HBD-CCC may scavenge nitric oxide, a blood-pressure regulating molecule, it may do so more slowly than other hemoproteins, leading to its safer profile.

Future studies will likely include more pre-clinical research to determine the safe and effective dosage range for RcoM-HBD-CCC in treating carbon monoxide poisoning. It could also form the basis for new research in other fields, including as an oxygen delivery therapy or blood substitute. This could include hemorrhagic shock, acute respiratory distress syndrome (ARDS), severe anemias, and the preservation of organs for transplantation.

Dr. Rose and Dean Gladwin are co-founders and directors of Globin Solutions, which has licensed technology based on RcoM from the University of Pittsburgh towards the development of a CO poisoning antidote. Dr. Rose is President and CEO of Globin Solutions. Globin Solutions has sponsored research agreements with UMB.