The Use of Blood Cells and Optical Cerebral Complex IV Redox States in a Porcine Model of CO Poisoning with Evaluation of Mitochondrial Therapy - Our overarching goal is to advance understanding of mitochondrial mechanisms of carbon
monoxide (CO) poisoning to develop diagnostics, therapeutics, and clinical trials. 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 (HBO) delivery system.
Despite the availability of HBO therapy centers in most major cities, inherent delays in access to and
initiation of therapy greatly limit efficacy. In fact, even with HBO oxygen therapy a substantial number
of surviving patients exhibit permanent neurocognitive impairments. This highlights an urgent need for
alternative therapy. In the present proposal, we propose to study novel antidotal therapies for CO
poisoning, based on our in vivo preliminary data that the use of a succinate prodrug relieves partial
CIV inhibition caused by CO poisoning. Another existing gap is the lack of effective biomarkers to
gauge severity, prognosis, and response to treatment. While a carboxyhemoglobin level is readily
available at most institutions, its use is limited only to confirm exposure with no predictive value. The
three main objectives our proposal seeks to address are: (1) extent of mitochondrial involvement for
diagnostics and therapies; (2) limitations of current biomarkers to gauge severity of disease and
treatment response; (3) lack of treatment strategies that target mitochondrial dysfunction to mitigate
long-term neurologic and cardiac disability. Specifically for this A1 submission, we recently developed
a novel survival swine model for CO poisoning with clinically relevant outcome metrics that include
behavioral, imaging, and biomolecular measures. We also have obtained additional noninvasive
optical data that also correlate with tissue respiration data. Another important feature of this proposal
is the evaluation of a new treatment strategy involving a mitochondrial prodrug with the potential to
shift existing treatment paradigm. We will also leverage our biomedical optics technology measuring
cerebral blood flow, oxygenation, COHb and redox states of CIV in real time which will allow us to
further elucidate the mechanisms of CO combined with repeat measures using two clinically relevant
exposure duration with varying doses as well as prolonged low dose CO exposure.
Aim 1 • To investigate the mitochondrial mechanisms that contribute to the neurologic and cardiac
injury with the use of blood cell as a liquid biomarker in both acute AND early chronic CO poisoning.
Aim 2 • Randomized, blinded pre-clinical intervention trial in swine models of CO poisoning to
compare an engineered succinate prodrug to standard therapy of hyperbaric oxygen (HBO).
