Novel drug for functional restoration of hypoxic heart

A novel oxygen-delivery therapeutic restored the function of oxygen-starved heart tissue in an animal model of global hypoxia in a new study published in the PLOS Biology. Unlike in previous studies, the new drug does not cause systemic side effects or overcorrect with excessive blood oxygenation, which can itself be toxic. The new drug, instead, delivers oxygen only to the tissues needing it the most.

The study is significant as low levels of oxygen is a major anger for body's tissues, and the heart is particularly sensitive to such hypoxic conditions leading to long-term tissue damage or even heart attacks.

The new drug, called OMX-CV, was developed by a biopharmaceutical company Omniox.

Emin Maltepe, associate professor of pediatrics at UCSF, and colleagues conducted the study to test the utility of a novel engineered protein derived from the heme-based nitric oxide (NO)/oxygen (H-NOX) family of bacterial proteins as an O₂ delivery biotherapeutic (Omniox-cardiovascular [OMX-CV]) for the hypoxic myocardium.

"Any tissue with compromised blood flow, whether due to trauma, stroke, or heart disease, could potentially be targeted by a treatment like this," said Maltepe.

Cardiovascular disease such as coronary artery disease can starve the heart of oxygen, triggering cardiac dysfunction or heart attacks in adults, but hypoxia in the heart is also a problem in children. According to the Centers for Disease Control and Prevention (CDC), about 10,000 children are born each year with a critical congenital heart defect. Many of these infants require heart surgery within their first year of life, during which blood may be temporarily removed from the heart, leaving the organ starved for oxygen.

Under normal conditions, the heart consumes more oxygen by weight than any other organ, and when oxygen levels are low, its demand soars even higher. The hypoxic heart pumps harder to deliver oxygen to the rest of the body, and paradoxically, requires more and more oxygen itself to maintain function.

An oxygen-delivering drug like OMX-CV could ease the physical stress of hypoxia and improve recovery following heart attacks or after open heart surgery in adults and children.

Scientists have tried to design ways to fight hypoxia by delivering oxygen on the back of hemoglobin, the protein that lets red blood cells shuttle oxygen throughout the body and also produces their scarlet color. But these treatments also carry a lot of baggage.

Hemoglobin-based drugs have proven too good at their jobs: they tend to flood the blood with excess oxygen that can itself cause serious tissue damage. Moreover, when outside the bounds of a red blood cell, hemoglobin can grab hold of nitric oxide, a natural muscle relaxant found in blood vessels. Vessels robbed of nitric oxide constrict, causing blood pressure to jump, raising the risk of heart attack and decreasing blood flow to important organs like the kidneys.

OMX-CV sidesteps these problems by employing an engineered bacterial protein known as H-NOX as its base, rather than hemoglobin. H-NOX proteins contain a "co-factor" called a heme group -- the same co-factor that gives hemoglobin its name -- which allows the protein to bind not only oxygen but also nitric oxide. By modifying the chemical structure of H-NOX proteins, Omniox scientists re-engineered them to hold tight to oxygen, but leave nitric oxide alone.

The researchers also showed that the modified proteins bind oxygen so tightly that they only relinquish their grip when they come across a severely hypoxic tissue.

"Kids change so much as they grow -- their drug metabolism changes dramatically year to year," said Maltepe. "After drugs are established in adults, pediatricians essentially have to experiment with kids to understand the treatments' toxicity profiles and proper dosing for different age groups." By initially designing and testing drugs with kids in mind, and taking measures such as using juvenile animal models of disease, the researchers hope to circumvent this unwieldy guesswork.

In their experiments, the scientists tested the effects of OMX-CV in acute hypoxia, and to ensure that their results would also apply to children, the researchers examined the drug's ability to supply oxygen to juvenile animal hearts, which share important anatomical and physiological characteristics with the hearts of human infants.

The researchers found that OMX-CV delivered oxygen to stressed hearts but not to tissues with an adequate oxygen supply. The OMX-CV infusion improved the hearts' ability to contract almost twofold better than their own baseline under hypoxic conditions, without the toxic effects of hemoglobin-based treatments. In contrast, the cardiac function of untreated animals deteriorated significantly over the hour-long study.

These impressive results were obtained with a relatively low dose of OMX-CV: each animal was treated with a dose equivalent to only 2 percent of the oxygen-carrying capacity of the blood's naturally circulating hemoglobin.

More preclinical research is needed before OMX-CV reaches human clinical trials. Looking forward, the researchers expect separate clinical trials for the drug's various applications.

"This treatment targets a fundamental problem in medicine --- in the ICU, for instance, you're always battling against tissues becoming hypoxic," said Maltepe, adding that the technology could someday form the basis of a more general blood replacement product, long considered a 'holy grail' of medicine.