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Novel lead compound advancement for mitigating halogen-induced mortality and morbidity.

Award Number: U01ES033263
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/16/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Novel lead compound advancement for mitigating halogen-induced mortality and morbidity. - Summary: Chlorine and bromine (Cl2 and Br2) are highly reactive and extremely toxic halogen gases that cause debilitating cardiopulmonary injury and death. Research from our previously funded ‘Identification of Therapeutic Lead Compounds U01’ provided published and preliminary data that identified calpain inhibitor (CI) as highly efficacious and safe antidote for Br2 inhalation-induced cardiopulmonary injury and mortality. These studies were carried out in our unique halogen exposure facility and the discovery of the mitigating agent was made possible by the development of the Cl2/Br2 exposure-induced rat model of acute cardiopulmonary damage and mortality. Using the whole body Br2 exposure rat model we demonstrated that the therapeutic action of CIs is caused by reduction in Br2 induced calpain activity, reduction of proteolysis of the myocardium and preservation of cardiac function leading to decreased mortality. Calpains (calcium dependent proteases) are activated by Br2/Br2 reactant-induced loss of cardiac sarcoendoplasmic reticulum Ca2+ ATPase, SERCA activity and subsequent catastrophic cytosolic Ca2+ overload. Intraperitoneal administration of a CI (that was selected from several commercially available CIs based on an ex-vivo high-throuput evaluation of cardiac calpain inhibition) 1h after Br2 exposure significantly mitigated acute increase in cardiac calpain activity, decreased Br2-induced mortality. Administration of CI significantly improved the clinical scores, heart rate and oxygen saturation. Br2-induced pulmonary edema and cardiac hypertrophy was also reduced. Several cardiovascular parameters such as blood pressure, ventricular pressure, cardiac output and other diastolic and systolic heart functions were improved in Br2-exposed animals after CI treatment. We have also initiated the studies on its various structural analogs. These structures were characterized for their improved solubility, bioavailability and stability. Preliminary data for their activity and cellular toxicity was also evaluated. Thus, as mentioned in the CounterACT FOA we provided validation of molecular targets for therapeutic development, proof of in vitro activity of the lead compound, preliminary in vivo proof-of-concept efficacy data, and preliminary adsorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) evaluations. Therefore, this lead compound ‘calpain inhibitor’ is now ready for optimization and we will also evaluate ADME/safety profile of the CI and its most effective analog. Optimization of CI/analog dose and delivery in a large animal model of halogen-induced cardiopulmonary injury will also be performed. These studies will allow the lead compound to move forward and help design the pivotal studies needed for regulatory FDA approval of CI under the animal rule.


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: 2026 ( Subtotal = $693,017 )
2026	2026	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Environmental Health	001	5	6/25/2026	NON-COMPETING CONTINUATION	$693,017
2026	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Environmental Health	000	4	2/5/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $693,017

Issue Date FY: 2025 ( Subtotal = $704,952 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Environmental Health	001	4	7/29/2025	NON-COMPETING CONTINUATION	$704,952
2025	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Environmental Health	000	3	4/16/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $704,952

Issue Date FY: 2024 ( Subtotal = $724,165 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Environmental Health	001	3	6/7/2024	NON-COMPETING CONTINUATION	$724,165
2024	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Environmental Health	000	2	12/1/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $724,165

Issue Date FY: 2023 ( Subtotal = $730,351 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Environmental Health	000	2	7/4/2023	NON-COMPETING CONTINUATION	$730,351
														Subtotal = $730,351

Issue Date FY: 2022 ( Subtotal = $742,499 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Environmental Health	000	1	9/16/2022	NEW	$742,499
														Subtotal = $742,499

Grand Total All Awards = $3,594,984

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Novel lead compound advancement for mitigating halogen-induced mortality and morbidity.

Award Number: U01ES033263

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/16/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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