Hemoglobin-based antidotes for the treatment of carbon monoxide poisoning - Project Summary/Abstract
Carbon monoxide (CO) poisoning remains a major cause of death and disability, affecting 50,000 persons
a year in the U.S. alone. Victims removed from fires or rescued after exposure to car or home generator exhaust
only have two options: 100% oxygen or transfer via ambulance or medical evacuation helicopter to a specialized
facility with emergency hyperbaric oxygen chamber. As there are approximately only 300 hyperbaric oxygen
centers available for CO poisoned patients, 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
long-term neurocognitive impairments. There is no point-of-care antidote for CO poisoning currently available.
In the present proposal, Globin Solutions, Inc. will seek to complete preclinical development of a novel
antidotal therapy for CO poisoning based on the use of high CO affinity derivatives of human hemoglobin,
including stripped hemoglobin (S-Hb) and NEM-modified hemoglobin (NEM-Hb). On-going work funded by the
NIH at the University of Pittsburgh demonstrates that extremely high affinity heme-based molecules can
sequester CO from red blood cells and tissue mitochondria to reverse the systemic hypoxia of CO poisoning.
We discovered a near-irreversible CO-binding affinity of mutationally engineered human neuroglobin (Ngb). This
molecule includes four point mutations (Ngb-H64Q-CCC) allowing for high concentration and intravenous
infusion. Ngb-H64Q-CCC binds CO ≈ 500 times more strongly than Hb. Infusions of Ngb-H64Q-CCC in CO-
poisoned mice enhanced CO removal from red blood cells in vivo from 25-minutes to 25-seconds, reversed
hypotension, 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. In further work, high
CO affinity derivatives of human hemoglobin, including stripped hemoglobin (S-Hb) and NEM-modified
hemoglobin (NEM-Hb) could be used for the treatment of CO poisoning. These molecules can be produced from
expired blood units at a low cost. Here we propose experiments to determine efficacy and safety of S-Hb and
NEM-Hb in the treatment of CO poisoning in our mouse models. The best performing molecule will be further
developed into a full IND enabling preclinical program: determine pharmacokinetics and safety profiles in mouse
and non-human primates; certified Good Manufacturing Procedure production at scale; and validating quality
and reproducibility assays. Globin Solutions, Inc. will leverage a recent Series A funding round to cost-share the
project expenses proposed in this grant for an IND application to the US FDA and to enable first in human trials.
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 the management of CO poisoning patients.
