Researchers have engineered a protein that reverses carbon monoxide poisoning in mice. There’s potential it might work for people, too.
CO poisoning is responsible for more than 50,000 emergency room visits in the United States each year, and is one of the leading global causes of poisoning death.
A colorless, odorless gas, CO is extremely effective at replacing oxygen molecules in hemoglobin, the oxygen carrying protein in blood. CO exposure also results in debilitating effects on the body and the brain, including cognitive deficits that in some cases can persist months or years after a poisoning event.
“Despite being the most common poisoning worldwide, we still do not have an effective antidote for CO exposure,” says Mark T. Gladwin, professor of internal medicine at the University of Pittsburgh School of Medicine. “Our protein is extraordinarily effective at scavenging CO from the blood, and could potentially prove to be a significant advance in the treatment of CO poisoning.”
1,200 times faster
Current treatment options for CO poisoning—administering 100 percent oxygen or using a pressurized hyperbaric chamber to administer oxygen at greater than normal air pressure—focus on trying to replace CO in blood with oxygen as quickly as possible.
However, both these treatments are only moderately effective. Moreover, transporting patients to a hyperbaric chamber requires a significant amount of time, and many poisoned patients may not be stable enough for this therapy.
For the current study, published in Science Translational Medicine, researchers looked at neuroglobin (Ngb), a hemoglobin-like protein present in the brain, and discovered it could bind CO with an unusually high affinity. Based on prior knowledge of how the protein works, they engineered a mutant version of the protein, called Ngb H64Q, that was an even better scavenger of CO.
In a purified sample of red blood cells infused with CO, they found that Ngb H64Q was 1,200 times faster at forcing CO to release itself from being bound to hemoglobin than just air alone.
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When tested in a mouse model of non-lethal CO poisoning, they found that Ngb H64Q was significantly better at removing CO from hemoglobin than 100-percent oxygen treatment.
The normal half-life of CO in humans after poisoning (the time it takes for half of the CO to be eliminated from the body) is 320 minutes, and even with 100-percent oxygen therapy, that time is 74 minutes. With the antidote therapy, the CO half-life was reduced to only 23 seconds.
In a mouse model with lethal levels of CO poisoning, seven out of eight mice treated with Ngb H64Q (87.5 percent) survived the duration of the experiment, while 10 percent or less survived in the control groups.
Additionally, the antidote restored blood pressure and improved the amount of oxygen that was present in tissues, suggesting that Ngb H64Q works by scavenging CO from hemoglobin and allowing oxygen to bind in its place, thus restoring normal oxygen delivery.
Clinical trials
Importantly, CO bound to Ngb H64Q was detected in the urine of mice shortly after treatment, which indicated that the rodents were able to excrete the antidote from the body without any major toxic effects.
“If approved, this antidote could be rapidly administered to victims in the field, eliminating costly delays that occur with current treatment options,” Gladwin said. “We still need extensive safety and efficacy testing before an antidote is available on the shelf, but our early results are very promising.”
Researchers plan to scale up their safety and efficacy testing in animal models and hope to advance to clinical trials within the next few years.
Other researchers from the University of Pittsburgh and from Wake Forest University are coauthors of the study. The National Institutes of Health, the Institute for Transfusion Medicine, and the Hemophilia Center of Western Pennsylvania; and the National Institutes of Health.
Source: University of Pittsburgh
