Development of a tissue-targeted non-thrombotic EPO derivative

About This Grant

“Development of a tissue-targeted non-thrombotic EPO derivative.” Chronic obstructive pulmonary disease (COPD) affects 16 million people in the US and is the third leading cause of death in the world, with an estimated 500 million cases worldwide. In the US the primary cause is cigarette smoking, but in most of the world the cause is air pollution. In this disease, the airways (bronchioles) are constricted and the alveoli are distended and never fully contract. Current treatments use drug inhalers that open up the airways, but these treatments are only partially effective. In addition, about 2 million of the US COPD patients are also anemic, so that oxygen delivery is particularly poor. Erythropoietin (EPO) is a hormone that mediates the body’s response to massive blood loss (hemorrhage). EPO is used to treat anemia in kidney failure, cancer, etc., based on its stimulation of red blood cell production. EPO also has a useful tissue-protective activity that can reduce effects of oxygen limitation that damage the heart, brain, and other tissues. However, EPO also enhances blood clotting and increases frequency of heart attacks, strokes and deep vein thrombosis when given to anemic patients. To address COPD and other problems of oxygen delivery, General Biologics is developing an engineered protein, termed “EPO-H” (EPO for Hypoxia), that retains the red blood cell producing and tissue-protective activities of EPO, but lacks the blood clotting side effects. EPO-H will also have a long plasma half-life, to allow for infrequent dosing, patient convenience, and reduced burden on the health care system. The net effect should be that, compared to current commercial versions of EPO, our protein (“EPO-H”) will maintain production of red blood cells, show increase neuroprotection, and have significantly reduced or eliminated blood-clotting site effects. Natural EPO is not currently given to COPD patients or patients with disorders such as cystic fibrosis or extreme Covid-19 requiring hospitalization and mechanical ventilation. Our experimental aims are: (1) General Biologics will produce engineered protein for all of the experiments and will test the proteins for blood-based surrogate markers of hypoxia resistance and blood-clotting, to establish a dose at which the therapeutic effect is expected but side effects are not.; (2) University of Maryland will demonstrate that EPO-H can promote survival of mice in a low- oxygen environment; and also (3) demonstrate that EPO-H does not enhance clot size in a mouse model of deep vein thrombosis, even though natural EPO does increase the size of blood clots in mice with deep vein thrombosis.