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Antidote for inhaled CO poisoning based on mutationally engineered neuroglobin

Award Number: R01HL125886
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2014
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Antidote for inhaled CO poisoning based on mutationally engineered neuroglobin - Carbon monoxide (CO) poisoning remains a major cause of death and disability, affecting 50,000 persons each year in the U.S. 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, inherent delays in access to and initiation of therapy greatly limit efficacy. 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 our initial work 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 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, 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 provided proof of concept that heme-based scavenger molecules with very high CO binding affinity can be developed as potential antidotes for CO poisoning. In the previous funding period, we continued the 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 showed how infusion of Ngb-H64Q-CCC can restore mitochondrial respiration in tissues and reverse CO-induced effects. We also set out to discover novel CO scavenger molecules which may have improved properties over our lead molecule. Our studies uncovered that RcoM, a bacterial CO sensor, has a high affinity towards CO and presents promising safety profiles in mouse models. In the present proposal we plan to further develop our Ngb-H64Q-CCC molecule, adding modifications that improve its CO affinity and stability for a safer toxicity profile. We also will engineer RcoM to obtain the smallest unit that can scavenge CO with high affinity and present optimal stability and safety properties. Finally, we will leverage all the knowledge on CO and oxygen binding achieved during our research program to develop novel oxygen carrier molecules that can serve as blood substitutes. 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $676,342 )
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Blood Diseases and Resources Research	000	11	6/27/2025	NON-COMPETING CONTINUATION	$676,342
														Subtotal = $676,342

Issue Date FY: 2024 ( Subtotal = $660,807 )
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Blood Diseases and Resources Research	002	10	6/24/2024	NON-COMPETING CONTINUATION	$660,807
2024	2023	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Blood Diseases and Resources Research	001	9	4/29/2024	COMPETING CONTINUATION	$132,045
2024	2022	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Blood Diseases and Resources Research	000	8	4/29/2024	NON-COMPETING CONTINUATION	-$132,045
														Subtotal = $660,807

Issue Date FY: 2023 ( Subtotal = $703,592 )
2023	2023	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Blood Diseases and Resources Research	001	9	8/25/2023	COMPETING CONTINUATION	$703,592
2023	2022	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Blood Diseases and Resources Research	000	8	5/27/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $703,592

Issue Date FY: 2022 ( Subtotal = $708,733 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Blood Diseases and Resources Research	001	8	6/15/2022	NON-COMPETING CONTINUATION	$70,873
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Blood Diseases and Resources Research	000	8	1/10/2022	NON-COMPETING CONTINUATION	$637,860
														Subtotal = $708,733

Issue Date FY: 2021 ( Subtotal = $708,733 )
2021	2021	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Blood Diseases and Resources Research	000	7	12/21/2020	NON-COMPETING CONTINUATION	$637,860
2021	2021	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Blood Diseases and Resources Research	001	7	5/14/2021	NON-COMPETING CONTINUATION	$70,873
														Subtotal = $708,733

Issue Date FY: 2020 ( Subtotal = $708,733 )
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Blood Diseases and Resources Research	001	6	1/28/2020	NON-COMPETING CONTINUATION	$35,437
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Blood Diseases and Resources Research	000	6	1/13/2020	NON-COMPETING CONTINUATION	$673,296
														Subtotal = $708,733

Issue Date FY: 2019 ( Subtotal = $722,858 )
2019	2019	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Blood Diseases and Resources Research	002	5	3/29/2019	COMPETING CONTINUATION	$13,897
2019	2019	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Blood Diseases and Resources Research	000	5	1/3/2019	COMPETING CONTINUATION	$722,858
2019	2018	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Blood Diseases and Resources Research	001	4	3/29/2019	NON-COMPETING CONTINUATION	-$13,897
														Subtotal = $722,858

Issue Date FY: 2018 ( Subtotal = $574,328 )
2018	2018	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Blood Diseases and Resources Research	001	4	6/23/2018	NON-COMPETING CONTINUATION	$11,487
2018	2018	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Blood Diseases and Resources Research	000	4	12/8/2017	NON-COMPETING CONTINUATION	$562,841
														Subtotal = $574,328

Issue Date FY: 2017 ( Subtotal = $582,028 )
2017	2017	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Blood Diseases and Resources Research	000	3	11/20/2016	NON-COMPETING CONTINUATION	$582,028
														Subtotal = $582,028

Issue Date FY: 2016 ( Subtotal = $595,927 )
2016	2016	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Blood Diseases and Resources Research	001	2	2/12/2016	NON-COMPETING CONTINUATION	$8,940
2016	2016	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Blood Diseases and Resources Research	000	2	1/8/2016	NON-COMPETING CONTINUATION	$586,987
														Subtotal = $595,927

Issue Date FY: 2015 ( Subtotal = $613,799 )
2015	2015	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Blood Diseases and Resources Research	000	1	11/24/2014	NEW	$613,799
														Subtotal = $613,799

Grand Total All Awards = $7,255,880

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Antidote for inhaled CO poisoning based on mutationally engineered neuroglobin

Award Number: R01HL125886

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/01/2014

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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