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Lack of oxygen is a major hazard for all tissues in your body, but the heart is particularly sensitive to such hypoxic conditions, which can lead to long-term tissue damage or even heart attacks.
In new studies conducted at UC San Francisco, a new therapeutic oxygen release therapy restored the function of oxygen-free cardiac tissue in an animal model of global hypoxia. Unlike its experimental predecessors, the new drug does not appear to cause systemic side effects or excessively correct with excessive oxygenation of the blood, which may itself be toxic. Instead, the new drug distributes its precious oxygen cargo only to the tissues that need it most.
"Any tissue whose blood flow is compromised, whether as a result of trauma, stroke, or heart disease, could potentially be targeted by such treatment." "said Emin Maltepe, MD, PhD, associate professor of pediatrics at UCSF and co-authored the paper.
The new drug, called OMX-CV, was developed by Omniox, Inc., a biopharmaceutical company developing oxygen-releasing therapeutics for the treatment of cancer, cardiovascular disease, trauma, and other conditions in the body. which a low oxygen content or hypoxia have a negative impact disease outcomes.
Omniox, which was one of the first start-up biotechnology companies to embark on the QB3 "Garage" incubator on Mission Bay's UCSF campus, in 2010, is Associated with Maltepe and other UCSF researchers to test the treatment, and published its findings on October 18, 2018, in the newspaper PLOS Biology.
Hypoxia During Heart Disease – An Uncontrolled Clinical Threat
Cardiovascular diseases such as coronary heart disease can starve the heart of oxygen, causing heart dysfunctions or heart attacks in adults, but heart hypoxia is also a problem in children. According to the Centers for Disease Control and Prevention (CDC), approximately 10,000 children are born each year with a critical congenital heart defect. Many of these infants have to undergo heart surgery in their first year of life, during which time blood can be temporarily removed from the heart, leaving the organ deprived of oxygen.
Under normal conditions, the heart consumes more oxygen in weight than any other organ and, when the oxygen level is low, the demand increases even more. The hypoxic heart pumps harder to deliver oxygen to the rest of the body and, paradoxically, needs more and more oxygen itself to maintain its function. An oxygen-releasing drug, such as OMX-CV, could alleviate the physical stress associated with hypoxia and improve recovery as a result of a heart attack or operation to open heart in the adult and the child.
Scientists have been trying to devise ways to combat hypoxia by providing oxygen to the back of hemoglobin, the protein that allows red blood cells to carry the blood. oxygen throughout the body and that also produces their scarlet color. But these treatments also carry a lot of luggage.
Hemoglobin-based drugs have proven to be too effective in their work: they tend to flood the blood with excess oxygen that can itself cause serious tissue damage. In addition, when it is outside of red blood cells, hemoglobin can attach to nitric oxide, a natural muscle relaxant found in blood vessels. Nitric oxide-depleted vessels contract, causing increased blood pressure, increased risk of heart attack, and decreased blood flow to important organs such as the kidneys.
OMX-CV avoids these problems by using a genetically modified bacterial protein called H-NOX as a base, rather than hemoglobin. H-NOX proteins contain a "co-factor" called hemic group – the same co-factor that gives its name to hemoglobin – which allows the protein to bind not only to oxygen, but also to nitric oxide. By altering the chemical structure of H-NOX proteins, Omniox scientists have modified their design to keep them under the influence of oxygen, while leaving nitric oxide alone.
Researchers have also shown that modified proteins bind oxygen so tightly that they only let go when they encounter severely hypoxic tissue.
"Unlike hemoglobin-based oxygen transporters, OMX-CV is designed to release oxygen only under pathological conditions," said Ana Krtolica, PhD, vice president of the research at Omniox and co-principal author of the article. "Relatively low doses of the drug transform the heart's ability to keep pace with severe hypoxia."
Targeted delivery to tissues lacking oxygen
The authors plan to use OMX-CV primarily to treat many conditions affected by hypoxia in adults, but the new study was also designed for pediatric applications. The research was conducted as part of the Initiative for the Development of Pediatric Drugs and Instruments, or iPD3, a collaboration between UCSF and the University of Maryland, Baltimore. This effort is aimed at designing and testing therapies specifically for pediatric care, rather than "transmitting" therapies designed for adults.
"Children change so much by growing up – their drug metabolism changes dramatically from one year to the next," Maltepe said. "Once medications are established in adults, pediatricians must essentially experiment with children to understand the toxicity profiles of the treatments and the appropriate dosage for different age groups." By initially designing and testing drugs for children, and taking action such as the use of animal models of disease in juvenile animals, researchers hope to circumvent this heavy assumption.
As part of their experiments, scientists tested the effects of OMX-CV on acute hypoxia and, to ensure that their findings could also be applied to children, they have examined the ability of this drug to provide oxygen to the hearts of juvenile animals, which share important anatomical and physiological features. with the hearts of human infants.
The researchers found that OMX-CV provided oxygen to stressed hearts, but not to tissues containing enough oxygen. The perfusion of OMX-CV improved the ability of hearts to contract almost twice as well as their own initial values under conditions of hypoxia, without the toxic effects of hemoglobin-based treatments. In contrast, the cardiac function of untreated animals has significantly deteriorated during the study of one hour.
These impressive results were obtained with a relatively low dose of OMX-CV: each animal was treated with a dose equivalent to only 2% of the oxygen carrying capacity of naturally circulating blood hemoglobin.
Current studies at UCSF, funded by the National Institutes of Health, using similar juvenile animal models, are designed to test whether OMX-CV can be developed to protect the hearts of infants undergoing cardiac bypass surgery.
A myriad of applicationss
Further preclinical research is needed before OMX-CV reaches clinical trials on humans. In the future, researchers expect separate clinical trials for different applications of the drug.
"Given the general need for oxygen in tissues and organs, hypoxia is associated with a number of pathological conditions," said Krtolica. Omniox develops preclinical programs focused on oxygen delivery in ischemic stroke, which compromises blood flow to the brain, as well as in cancer.
"This treatment targets a fundamental problem of medicine: in ICU, for example, you still struggle against tissue hypoxia," said Maltepe, adding that technology might one day be the basis of a a more general blood substitute considered a "holy grail" of medicine.
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