In the 16th century, Paracelsus—the father of modern toxicology—wrote that “all things are poison and nothing is without poison; the dose alone makes a thing not poison.” While it’s conceivable that too much of a good thing, such as water or oxygen, could be fatal, the opposite—that smaller quantities of a bad thing might be beneficial—may be harder to believe. But four centuries after Paracelsus shared this idea, two researchers decided to apply the more counterintuitive notion of Paracelsus’ dogma for a notoriously toxic chemical: carbon monoxide (CO).
Low-Dose CO Therapies
While CO is known to many as the colorless, odorless, and tasteless “suicide gas” that sends more than 50,000 Americans to the emergency room annually, it only becomes toxic at high concentrations, around 10,000 parts per million. However, Augustine Choi and Leo Otterbein (Figure 1: Photo courtesy of the Beth Israel Deaconess Medical Center), the two scientists who pioneered much of the current research on therapeutic uses of CO, focused on much lower doses of the gas, around 250 parts per million. Although the idea that CO could be used therapeutically was suggested as early as 1932, it wasn’t studied in detail until the late 1990s, when Choi and Otterbein delved into the mechanism.
At the time, Choi (now dean of Weill Cornell Medicine in New York City) and Otterbein (currently an associate professor at Harvard Medical School) were at the University of Pittsburgh, Pennsylvania; Choi was a professor and Otterbein was his graduate student. Scientists were just beginning to understand the biological function of an enzyme called heme oxygenase, which is thought to protect our lungs from many pollutants. Heme oxygenase is known to convert heme—the central platform of hemoglobin—into three components: iron, a pigment called biliverdin that contributes the greenish color to bruises, and CO. It is through this simple, natural process that our human bodies can generate approximately
10 mm of CO daily.
Based on a few years of rigorous experimentation during his Ph.D. degree studies, Otterbein determined that a low dose of CO could prevent rats from suffering lung injury. Later on, researchers found that CO not only could be helpful in treating inflammatory conditions of the lung but also could reduce the risk of organ rejection after transplantation. Moreover, CO could alleviate conditions such as sickle cell anemia, neurological diseases, pancreatitis, hepatitis, and many other indications. Most of this research has been performed in animal models, and human clinical trials with low dosages of CO are ongoing.
Delivering the CO Gas
The traditional way of delivering CO is in a gaseous form. Currently, patients enrolled in CO trials need to go into a registered medical center to receive treatment. “It’s not any more difficult for them to get treated than it is for cancer patients to go to the hospital for their chemotherapy,” says Choi. “Patients come to the clinic and breathe in CO for about two to three hours.”
However, delivering gas to patients who need chronic treatment might not be practical. “From a clinical standpoint, it’s difficult to give accurate doses of the gas,” explains Otterbein, who has continued research on CO. “Breathing a gas just isn’t as easy as taking a pill.”
Already, companies are developing different ways to deliver CO. Proterris, a Boston-based biopharmaceutical company founded by Choi and Jeff Wager of Apeiron Partners LLC, has focused mainly on developing CO gas for idiopathic pulmonary fibrosis—a lung condition that is often misdiagnosed and does not have a cure—and tissue damage caused by a lack of oxygen delivery, otherwise known as ischemia reperfusion injury.
Here, the innovative treatment uses CO gas at a low therapeutic dose. Proterris has also worked on developing single-use canisters and inhalation devices that make it impossible to overdose on CO. Having such safety features would demonstrate that low-dose inhaled CO can be consistently delivered safely to patients. To date, phase I trials have been performed for inhaled CO in patients with idiopathic pulmonary fibrosis and acute respiratory distress disorder .
CO Delivery Via Carrier Molecules
Recently, Proterris acquired Alfama, a company in Portugal also working on CO therapies. But, instead of developing treatments in gaseous form, Alfama is tethering CO to carrier molecules and developing what are called CO-releasing molecules (CORMs). The benefit of using CORMs is that they can deliver CO in a very targeted manner, thus controlling dosing. In CORMs, CO can be transported on small molecules, which are usually transition metals. Small metal CORMs usually have some toxicity effects, but those developed by Alfama have very low toxicity issues, according to Wager. (The metal being used in this case is proprietary.) Currently, these CORMs are still being tested and validated in toxicology studies before being used in clinical trials for conditions such as acute liver failure and nonalcoholic fatty liver disease.
Similar to Alfama, Prolong Pharmaceuticals LLC—a biotechnology company headquartered in New Jersey—is developing a CORM via a different approach. Whereas Alfama is using small molecule carriers, Prolong is developing a large-molecule CORM called SANGUINATE to treat sickle cell anemia—a hereditary disease that causes the production of abnormally shaped red blood cells—and its comorbidities (Figure 2:Photo courtesy of Prolong Pharmaceuticals LLC). In the case of SANGUINATE, a molecule of polyethylene glycol is covalently attached to a hemoglobin molecule that can deliver both CO (to reduce inflammation) and oxygen. “We have been encouraged by [the drug’s] unique ability to transfer both CO and oxygen effectively to sickled red blood cells, resulting in an increased duration of unsickling—or returning of the red blood cells to a more normal shape,” says Glenn Kazo, Prolong’s president and cofounder (Figure 3: Photo courtesy of Prolong Pharmaceuticals LLC).
To date, Prolong has completed clinical trials that have studied the safety and efficacy of SANGUINATE , , and phase III trials are in the works. The drug is delivered intravenously and, for most indications, on a short-term basis to patients with sickle cell disease and related conditions. In addition, although Prolong has studied SANGUINATE’s benefits only for sickle cell disease, Kazo suggests that the drug “may also have potential benefits for treating a variety of diseases where ischemia and inflammation play a role.”
CO in Beverage Form
Hillhurst Biopharmaceuticals, Inc., based outside Los Angeles, California, has yet another approach for getting CO to patients: they are developing a proprietary liquid formulation of CO for patients suffering from traumatic brain injuries—including concussions, for which there is no current treatment—and sickle cell disease, as well as those who have had kidney transplants. The liquid formation was invented by hematologists Edward Gomperts and Henry Forman at Children’s Hospital Los Angeles.
Andrew Gomperts, chief executive of Hillhurst, recognized that there is a major challenge in delivering CO (Figure 4). “Having a tank of [CO] in your home is not the right way to go for patients who need to be treated for a chronic disease,” says Gomperts. Already, some hospitals are concerned about having CO tanks in case people are unsuspectingly exposed to the gas. “And, even if a patient doesn’t have an acute or chronic use for carbon monoxide, you might as well have an easy-to-use home drug,” he adds.
In addition, developing CO in a liquid form isn’t easy; the gas behaves in water similarly to the way oil behaves when mixed with vinegar—and that process represents the invention in Hillhurst’s product. The beverages are currently in the preclinical phase of development, but research shows that Hillhurst’s beverage, an intravenous formulation of CO, is demonstrating the same degree of efficacy as CO gas.
Otterbein, who also acts as a consultant for Prolong, was initially skeptical when presented with the idea of drinking CO, but he became convinced when the data started showing that the drink was just as effective as inhaling gas. “It’s something that can, one day, be put on the sidelines during football games,” he says. And CO’s antibacterial properties can keep the drink from going bad.
Fighting the CO Stigma
While scientists and companies who have been intrigued by the promise of CO are working to develop therapeutic CO in myriad ways, one major challenge they need to overcome is the long-held stigma that CO has toxic effects. Whereas toxic doses can send patients to the emergency room, low-dose CO is, so far, proving to be safe and efficacious.
More data and trials are needed to validate the therapeutic potential of CO, but the therapy looks promising. “I think in about three to five years we’ll have a better understanding of the landscape of carbon monoxide as a drug,” predicts Choi.
- M. A. Perrella. Safety study of inhaled carbon monoxide to treat acute respiratory distress syndrome (ARDS). Brigham and Women’s Hospital. Tech. Rep. NCT02425579, Boston, MA. [Online]. Available: https://clinicaltrials.gov/ct2/show/NCT02425579?term=ARDS+
- H. Misra, J. Lickliter, F. Kazo, and A. Abuchowski, “PEGylated carboxyhemoglobin bovine (SANGUINATE): Results of a phase I clinical trial,” Artif. Organs, vol. 38, no. 8, pp. 702–707, Aug. 2014.
- Prolong Pharmaceuticals. Study of SANGUINATE versus hydroxyurea in sickle cell disease (SCD) patients. Prolong Pharmaceuticals LLC. Tech. Rep. NCT01848925, South Plainfield, NJ. [Online]. Available: https://clinicaltrials.gov/ct2/show/NCT01848925?term=sanguinate&rank=3