Carbon monoxide (CO) poisoning remains a major cause of death and disability, affecting 50,000 people per year in the United States alone. Patients removed from fires or following exposure to car and home generator exhaust are placed on 100% oxygen and transferred to a facility with a hyperbaric oxygen delivery system. Despite the availability of hyberbaric therapy centers in most major cities, inherent delays in access to and initiation of therapy greatly limit efficacy. In fact, even with hyberbaric oxygen therapy, 1-2% of patients die and >25% of surviving patients exhibit neurocognitive impairments. There is currently no point-of-care antidote for CO poisoning available clinically. In the present proposal, we continue our studies developing novel antidotal therapies for CO poisoning, based on our findings that extremely high affinity heme-based molecules can bind and sequester CO from red blood cells and tissue mitochondria to reverse the systemic ischemia of CO poisoning. In the previous funding period, we discovered a surprising and near-irreversible CO-binding affinity of mutationally engineered human neuroglobin (Ngb). Ngb is a six-coordinate hemoprotein, with the heme iron coordinated by two histidine residues. We mutated the distal histidine to glutamine (H64Q) and three surface-thiols to form a five-coordinate heme protein (Ngb-H64Q-CCC) that has very high solubility (>10mM), allowing for high concentration and intravenous infusion. This molecule binds CO ~ 500 times more strongly than hemoglobin. Infusions of Ngb- H64Q-CCC in CO-poisoned mice enhanced CO removal from red blood cells in vivo from 25 minutes to 25 seconds, restored heart rate and blood pressure, increased survival from less than 10% to over 85%, and were followed by rapid renal elimination of CO-bound Ngb-H64Q-CCC. These findings provide proof-of-concept that heme-based scavenger molecules with very high CO binding affinity can be developed as potential antidotes for CO poisoning.
We aim to continue development of our Ngb-H64Q-CCC molecule, evaluating efficacy on the restoration of cellular aerobic respiration, safety, and acute- and long-term effects on cardiovascular and cognitive function and survival in pre-clinical models, and scaling production of recombinant protein for clinical development. We also aim to further discover novel CO scavenger small molecules, based on knowledge derived from our previous studies. We will mutationally engineer heme-bound, small 6-12 amino acid peptides derived from microperoxidase, with and without iron-to- cobalt metal substitutions to limit redox reactivity and enhance CO affinity. Overall, these proposed studies are in keeping with the mission of the NHLBI and NIH to advance highly impactful, significant, and novel studies that have great potential to improve the public health. Support for these proposed studies has the potential to change our current paradigm for therapy of CO poisoning.
Carbon monoxide poisoning results in an estimated 50,000 emergency department visits in the United States annually and is one of the leading causes of poisoning death. In the current proposal we aim to develop a specific antidotal therapy that can be given in the field by paramedics that can remove carbon monoxide from red blood cells, tissues, and heart and brain mitochondria within minutes. The availability of an effective antidote for carbon monoxide has the potential to the dramatically change the current treatment and has the potential to substantially decrease death and disability caused from this common poisoning.
|Du, Mengtian; Van Ness, Sarah; Gordeuk, Victor et al. (2018) Biomarker signatures of sickle cell disease severity. Blood Cells Mol Dis 72:1-9|
|Goncharov, Dmitry A; Goncharova, Elena A; Tofovic, Stevan P et al. (2018) Metformin Therapy for Pulmonary Hypertension Associated with Heart Failure with Preserved Ejection Fraction versus Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 198:681-684|
|Rose, Jason J; Nouraie, Mehdi; Gauthier, Marc C et al. (2018) Clinical Outcomes and Mortality Impact of Hyperbaric Oxygen Therapy in Patients With Carbon Monoxide Poisoning. Crit Care Med 46:e649-e655|
|Remy, Kenneth E; Cortés-Puch, Irene; Solomon, Steven B et al. (2018) Haptoglobin improves shock, lung injury, and survival in canine pneumonia. JCI Insight 3:|
|Kim-Campbell, Nahmah; Gretchen, Catherine; Callaway, Clifton et al. (2017) Cell-Free Plasma Hemoglobin and Male Gender Are Risk Factors for Acute Kidney Injury in Low Risk Children Undergoing Cardiopulmonary Bypass. Crit Care Med 45:e1123-e1130|
|Meijles, Daniel N; Sahoo, Sanghamitra; Al Ghouleh, Imad et al. (2017) The matricellular protein TSP1 promotes human and mouse endothelial cell senescence through CD47 and Nox1. Sci Signal 10:|
|Gladwin, Mark T (2017) Translational Advances in the Field of Pulmonary Hypertension Bench to Bedside: How Fundamental Discoveries in Science Are Advancing Our Understanding and Therapy of Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 195:1-3|
|Amdahl, Matthew B; DeMartino, Anthony W; Tejero, Jesús et al. (2017) Cytoglobin at the Crossroads of Vascular Remodeling. Arterioscler Thromb Vasc Biol 37:1803-1805|
|Kato, Gregory J; Steinberg, Martin H; Gladwin, Mark T (2017) Intravascular hemolysis and the pathophysiology of sickle cell disease. J Clin Invest 127:750-760|
|Gladwin, Mark T (2017) How Red Blood Cells Process Nitric Oxide: Evidence for the Nitrite Hypothesis. Circulation 135:177-179|
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