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LR-IL-22 for Mitigation and Management of Radiation Injuries

Award Number: U01AI172885
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/20/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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LR-IL-22 for Mitigation and Management of Radiation Injuries - Abstract: Mitigation of damage caused by total body irradiation (TBI) or partial body irradiation (PBI) requires targeting the acute gastrointestinal syndrome. Parenteral administration of radiation mitigators for the hematopoietic syndrome may also ameliorate the gastrointestinal syndrome; however, drug delivery to the intestinal crypts is ineffective due to irradiation damage to the intestinal microvasculature. We have demonstrated that oral administration of engineered Lactobacillus reuteri, which produces and releases IL-22 (LR-IL-22), ameliorates the TBI induced acute gastrointestinal syndrome. Effective mitigation is associated with preservation of Lgr5+ intestinal crypt stem cells and their regeneration capacity. We will now establish the underlying mechanism of radiation mitigation by LR-IL-22, and will develop a microbial therapeutic with enhanced safety and efficacy. Preliminary data demonstrate that LR-IL-22 restores irradiation-induced suppression of gene transcription in Lgr5+ stem cells. TBI reduces expression of the aryl hydrocarbon receptor (AhR) in the intestine and its generation of downstream products, including IL-22. We hypothesize that TBI-induced intestinal damage will be further mitigated by combining LR-IL-22 with a probiotic (R2Ic) that naturally induces AhR to stimulate recovery of intrinsic IL-22 levels. Furthermore, we will establish that priming the release of IL-22 by our engineered probiotic increases therapeutic efficacy and the biological and environmental safety profiles. The First Specific Aim tests the hypothesis that LR-IL-22 restores radiation suppressed transcription at the molecular level in Lgr5+GFP+ intestinal stem cells. The Second Specific Aim tests the hypothesis that the activation of AhR in irradiation weakened cells by LR-IL-22 is further boosted by oral gavage of R2Ic to induce intrinsic IL-22 production. The Third Specific Aim addresses the need to provide biological and environmental containment of LR-IL-22, while improving the therapeutic efficacy. Successful completion of the proposed studies will lead to translation of LR-IL-22 to the National stockpile, as an effective mitigator of the acute radiation induced gastrointestinal syndrome.


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 = $545,451 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	4	1/9/2026	NON-COMPETING CONTINUATION	$545,451
														Subtotal = $545,451

Issue Date FY: 2025 ( Subtotal = $628,726 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	001	3	4/4/2025	SUPPLEMENT FOR EXPANSION	$99,639
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	3	1/15/2025	NON-COMPETING CONTINUATION	$529,087
														Subtotal = $628,726

Issue Date FY: 2024 ( Subtotal = $645,090 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	002	2	5/15/2024	NON-COMPETING CONTINUATION	$54,544
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	003	2	5/22/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	001	2	2/7/2024	SUPPLEMENT FOR EXPANSION	$99,639
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	2	11/20/2023	NON-COMPETING CONTINUATION	$490,907
														Subtotal = $645,090

Issue Date FY: 2023 ( Subtotal = $560,201 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	1	12/20/2022	NEW	$560,201
														Subtotal = $560,201

Grand Total All Awards = $2,379,468

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LR-IL-22 for Mitigation and Management of Radiation Injuries

Award Number: U01AI172885

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 12/20/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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