In the sixteenth century, Paracelsus—the father of modern toxicology—wrote, “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—might 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.
While carbon monoxide (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, right; Photo credit: Beth Israel Deaconess Medical Center), the two scientists who pioneered much of this research on therapeutic uses of CO, had their eye 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 the 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; Choi was a professor and Otterbein 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—to three components: iron, a pigment called biliverdin that contributes the green-ish color to bruises, and carbon monoxide. It is through this simple, natural process that our human bodies can generate approximately 10 milliliters of CO daily.
Through a few years of rigorous experimentation during his PhD, Otterbein was able to determine that low dose carbon monoxide was able to prevent rats from lung injury. Later on, researchers found that CO could not only be helpful in treating inflammatory conditions of the lung, but that it could also reduce the risk of organ rejection after transplantation. Moreover, it could alleviate diseases such as sickle cell anemia, neurological diseases, pancreatitis, hepatitis, and many other indications. The majority of this research has been done in animal models, and human clinical trials with low-dose carbon monoxide are ongoing.
The traditional way of delivering carbon monoxide is in a gaseous form. Currently, patients enrolled in CO trials need to go into a registered medical center to receive their 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,” says Otterbein, who has continued research on carbon monoxide. “Breathing a gas just isn’t as easy as taking a pill.”
Already, companies are developing different ways to deliver carbon monoxide.
Proterris, a Boston-based biopharmaceutical company founded by Choi and Jeff Wager of Apeiron Partners LLC, has mostly focused on developing CO gas for idiopathic pulmonary fibrosis—a lung condition that is often misdiagnosed and does not have a cure—and tissue damaged caused by a lack of oxygen delivery, otherwise known as ischemia reperfusion injury.
Here, the innovation is using carbon monoxide gas at a low, therapeutic dose. Proterris has also worked on developing single-use canisters and inhalation devices that would 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 done for inhaled CO in patients with idiopathic pulmonary fibrosis and acute respiratory distress disorder .
Recently, Proterris acquired Alfama, a company in Portugal also developing CO therapies. But instead of developing gas, Alfama is tethering carbon monoxide to carrier molecules and developing what are called carbon monoxide releasing molecules, or 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 non-alcoholic fatty liver disease.
Similar to Alfama, Prolong Pharmaceuticals LLC—a biotechnology company headquartered in New Jersey—is developing a CORM using 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, above). In the case of SANGUINATE, a molecule of polyethylene glycol is covalently attached to a hemoglobin molecule that can deliver both carbon monoxide (to reduce inflammation) and oxygen (to deliver 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, president and co-founder of Prolong Pharmaceuticals (Figure 3, right; Photo Credit: Prolong Pharmaceuticals LLC).
To date, Prolong has completed clinical trials that have studied the safety and efficacy [2, 3] of SANGUINATE, and Phase III trials are in the works. The drug is delivered by IV, and for most indications, will be delivered on a short-term basis to patients with sickle-cell disease and related conditions. And although Prolong has only studied SANGUINATE’s benefits for sickle cell disease, the drug “may also have potential benefits for treating a variety of diseases where ischemia and inflammation play a role,” says Kazo.
Hillhurst Biopharmaceuticals Inc. based outside Los Angeles, California, has yet another approach in getting carbon monoxide to patients: they are developing a proprietary liquid formulation of carbon monoxide for patients who are suffering from traumatic brain injuries— including concussions, for which there is no current treatment—sickle cell disease, and kidney transplant. The liquid formation was invented by hematologists Edward Gomperts and Henry Forman at Children’s Hospital Los Angeles.
Andrew Gomperts, the chief executive of Hillhurst, recognized that there is a major challenge in delivering carbon monoxide (Figure 4, right; Photo Credit: Hillhurst Biopharmaceuticals, Inc.). “Having a tank of carbon monoxide 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 carbon monoxide 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.”
But developing carbon monoxide in a liquid form isn’t easy; the gas behaves in water similarly to how oil behaves when mixed with vinegar—and that’s where the invention lies in Hillhurst’s product. These beverages are currently in the preclinical phase of development, but research is showing that Hillhurst’s beverage, an IV formulation of carbon monoxide, 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 carbon monoxide, but 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 because carbon monoxide has antibacterial properties, it can keep the drink from going bad.
While scientists and companies who have been intrigued by the promise of carbon monoxide are working to develop therapeutic CO in myriad different ways, one major challenge they need to over-ride is the long-held stigma that CO has toxic effects. Whereas toxic doses can send patients to the emergency room, low-dose carbon monoxide is, so far, showing to be safe and efficacious.
More data and trials are needed to validate the therapeutic potential of carbon monoxide, 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,” says Choi.
- Safety Study of Inhaled Carbon Monoxide to Treat Acute Respiratory Distress Syndrome (ARDS).
- H. Misra, J. Lickliter, F. Kazo, A. Abuchowski. PEGylated carboxyhemoglobin bovine (SANGUINATE): results of a phase I clinical trial. Artif. Organs. 2014 Aug. 38(8):702-7. doi: 10.1111/aor.12341.
- Study of SANGUINATE™ Versus Hydroxyurea in Sickle Cell Disease (SCD) Patients.