New protein quickly and safely treats carbon monoxide poisoning

Carbon monoxide is also known as the "silent killer" because it has no odor, taste, or color. In the United States alone, it admits more than 50,000 people to emergency rooms each year and kills about 1,500. The majority of exposures happen after fires, faulty heaters, or gasoline-powered appliances venting the gas into a space that is confined. Without immediate medical attention, the results are deadly. Even survivors aren't necessarily out of the woods. Nearly half of them experience permanent brain and heart damage, despite the most effective treatments available today.

A new achievement by researchers at the University of Maryland School of Medicine is redefining that story. They developed an engineered protein treatment that can efficiently reduce carbon monoxide levels in the blood quicker than oxygen treatment, without the toxic side effects that have limited current methods.

The RcoM-HBD-CCC protein, which they had genetically modified, is a redesigned version of a molecule that exists naturally in bacteria. In nature, the protein enables microbes to detect trace levels of carbon monoxide in the environment. Researchers designed a version of the molecule that can act as a sponge for the deadly gas inside the human body by remodeling the molecule.

Mice experiments showed that the therapy was quick to work, eliminating carbon monoxide from red blood cells and excreting it from the body through the urine. The protein was not only effective but also safe, inducing barely noticeable blood pressure fluctuations.

"In contrast with most other protein therapy treatments, we discovered that the compound caused very minimal shift in blood pressure, and this was an exciting finding and added to the promise of this new molecule being applicable in a clinical context," said Mark T. Gladwin, MD, Dean of the medical school and Vice President for Medical Affairs at the University of Maryland, Baltimore.

Gladwin said that the molecule could become "a rapid, intravenous antidote for carbon monoxide that could be given in the emergency department or even in the field by first-responders."

To understand why the new treatment is so exciting, it helps to learn how carbon monoxide kills. In normal conditions, air oxygen is bound to hemoglobin, the red blood protein tasked with delivering it to tissue. Carbon monoxide vies for the exact same binding sites on hemoglobin but attaches 200 to 400 times more strongly. Under the control of the poisonous gas, oxygen delivery precipitously falls. Organs dependent on uninterrupted oxygen supply—heart and brain among them—become dysfunctional in a matter of minutes.

The existing treatments entail administering 100 percent oxygen to the patients, either in a mask or via a hyperbaric chamber. Oxygen therapy hastens the elimination of carbon monoxide, yet is far from flawless. Even with pure oxygen, blood takes about an hour to eliminate half of the carbon monoxide, compared to well over five hours with no treatment. The new protein therapy, in comparison, eliminated half of the carbon monoxide in under a minute in laboratory tests.

This molecule potentially could be a game-changer because it can eliminate carbon monoxide from the body quickly and safely with very little risk of off-target side effects," said Jason J. Rose, MD, MBA, Associate Professor of Medicine and Division Chief of Pulmonary, Critical Care & Sleep Medicine at the University of Maryland.

The researchers in Maryland aimed to design "scavenger" proteins. They are custom-made molecules such as hemoglobin that grab hold of carbon monoxide more tightly than the gas binds with native hemoglobin. Injected into the bloodstream, the scavenger mops up carbon monoxide and eliminates it, freeing the body's red blood cells to return to their role of ferrying oxygen.

Always, however, the challenge has been side effects. The majority of scavenger proteins also bind nitric oxide, a naturally occurring vasodilator that regulates pressure. Vessels constrict and blood pressure rises perilously when too much nitric oxide is removed.

In past experiments, this has worked against treatments made of hemoproteins. RcoM-HBD-CCC was not like that. In trials, it showed far less reactivity to nitric oxide than typical hemoglobins. The result was a safer profile, with virtually no rise in blood pressure even at elevated doses.

The engineered protein exhibits an unusual combination of characteristics that rarely come together at the same time. It possesses an unusually strong binding affinity for carbon monoxide, with a 2.8 × 10¹⁰ binding constant. That is remarkably sticky to the gas. Its selectivity for carbon monoxide over oxygen was more than 190,000-fold, i.e., it essentially ignores oxygen but retains the toxin. The protein is also heat-stable, retaining its structure up to 72 °C, and is resistant to autoxidation, a reaction that would otherwise kill comparable molecules.

When introduced into the body, RcoM-HBD-CCC rapidly bound to carbon monoxide from hemoglobin in red blood cells, and the conjugated complex was cleared in urine without any toxicity. That rapid clearance is both a virtue and a reduced risk of building up to toxic levels.

The delicate balance of the molecule—excellent activity against carbon monoxide, poor activity against oxygen and nitric oxide—is where it differentiates from previous attempts. By protecting nitric oxide signaling, it reduces the potential for hypertension and other cardiovascular issues typically found in protein-based therapies.

The success with mice is only the start, but the findings are poised to open new doors. Future research will focus on maximizing the dosage and tolerability in larger preclinical studies. If results hold, the treatment can move to human trials. Beyond poisoning cases, researchers see other uses.

Severe anemia, hemorrhagic shock, and acute respiratory distress syndrome are all scenarios where rapid restoration of oxygen delivery can be lifesaving. The protein may also be employed as an emergency blood substitute or as a way to store donated organs for transplantation.

"With the positive results, we also envision a possibility for RcoM-HBD-CCC to be used in other areas, like a blood substitute in hemorrhagic shock or critical anemia," Rose stated. The only existing therapy for patients is still oxygen therapy. But with this study, things are looking bright for emergency treatment of carbon monoxide poisoning.

Research findings are available online in the journal PNAS.

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