# The Use of Blood Cells as a Biomarker in a Porcine Model of CO Poisoning with Evaluation of an Engineered Succinate-Prodrug

> **NIH NIH R56** · UNIVERSITY OF PENNSYLVANIA · 2021 · $697,310

## Abstract

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 ex vivo findings 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) limited mechanistic understanding of the key
role the mitochondria has in CO poisoning; (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. This project will define the mitochondrial
pathways involved in CO poisoning using blood cells compared against brain and cardiac tissue in a
porcine model of CO poisoning, furthering the mechanistic understanding of CO poisoning. 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. To achieve these
objectives, a large animal trial in a porcine model of CO poisoning is proposed with the following
aims:
Aim 1 • To establish the mitochondrial mechanisms that contribute to the neurologic and
cardiac injury that occur in CO poisoning and assess blood cell mitochondrial function as a
potential liquid biomarker.
Aim 2 • Randomized, blinded pre-clinical intervention trial in porcine models of CO poisoning
to compare an engineered succinate prodrug to standard therapy of hyperbaric oxygen (HBO).

## Key facts

- **NIH application ID:** 10276252
- **Project number:** 1R56HL158696-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** DAVID H JANG
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $697,310
- **Award type:** 1
- **Project period:** 2021-09-20 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10276252

## Citation

> US National Institutes of Health, RePORTER application 10276252, The Use of Blood Cells as a Biomarker in a Porcine Model of CO Poisoning with Evaluation of an Engineered Succinate-Prodrug (1R56HL158696-01). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10276252. Licensed CC0.

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