Monday, December 30, 2024 12/30/2024

Developing second generation SCID pig models: filling the gaps to improve translation of therapeutics in regenerative medicine

Award Number: R24OD028748
ORGANIZATION: OFFICE OF THE DIRECTOR, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract: The promise of stem cell therapies has not been fully realized, due in part to a paucity of appropriate pre-clinical models. The pig is an excellent model of human biology, due to similarities of size, physiology, and genetics, and in some cases may be superior to rodent models, which often fail to provide data which effectively translates to human clinical trials. Thus, pig models that more accurately model humans are critically needed to improve research outcomes of regenerative medicine therapeutics and maximize safe translation to the clinic. As SCID pig models show promise in xenograft studies, this establishes further needs for humanized pigs as second-generation models and improved methods to routinely rear immunodeficient pigs for measurement of survival, safety, and potential efficacy of implanted therapeutic cells. We are focused on generating such new knowledge and demonstrating SCID pig use in preclinical regenerative medicine research. We have developed biocontainment facilities and protocols to raise Artemis (ART)-mutant SCID pigs. We have demonstrated this model's significance through successful ectopic engraftment with human induced pluripotent stem cells (iPSC) and human cancer cell lines, as well as survival of orthotopically transplanted human skin. To improve the model, we mutated the Interleukin 2 Receptor gamma gene (IL2RG) in a male ART null background. The ART null IL2RG null pig has the expected T-B-NK- phenotype, and we have successfully demonstrated partial human immune system development in these ART-IL2RG pigs. Thus we have taken pioneering steps to establish a pig SCID model, but improvements in xenograft safety/efficacy testing and humanization remain prerequisites to harness these research models for translational medicine. The specific objectives of this application are to a) validate SCID pig models for preclinical testing of cell and tissue xenografts, b) use multiple novel humanization approaches to determine the extent of human hematopoiesis in SCID pigs, and c) establish second-generation SCID pig model management protocols at multiple biocontainment facilities. The rationale for the proposed research is that our outbred SCID pig may more accurately reflect how proposed stem cell derived therapies will function in humans compared to mice. This project is innovative because we will use an integrated approach to combine research on the model's xenograft potential with research focused on protocols for improving the use of immunodeficient pigs, including humanization methods. We expect that the successful completion of this project will create genetic resources, data on xenograft and humanization rates, and associated animal procedures that will be highly desirable for SCID based modeling for research on the safety and efficacy of stem cell therapeutics. These unique resources are expected to have a significant impact in accelerating the translation of regenerative medicine research into the clinic.


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: 2023 ( Subtotal = $730,384 )
2023	2023	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Research Infrastructure Programs	000	4	1/11/2023	NON-COMPETING CONTINUATION	$657,346
2023	2023	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Research Infrastructure Programs	001	4	3/6/2023	NON-COMPETING CONTINUATION	$73,038
														Subtotal = $730,384

Issue Date FY: 2022 ( Subtotal = $738,090 )
2022	2022	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Research Infrastructure Programs	000	3	2/1/2022	NON-COMPETING CONTINUATION	$664,282
2022	2022	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Research Infrastructure Programs	001	3	5/17/2022	NON-COMPETING CONTINUATION	$73,808
														Subtotal = $738,090

Issue Date FY: 2021 ( Subtotal = $987,743 )
2021	2021	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Research Infrastructure Programs	000	2	2/4/2021	NON-COMPETING CONTINUATION	$668,083
2021	2021	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Research Infrastructure Programs	002	2	7/31/2021	SUPPLEMENT FOR EXPANSION	$245,428
2021	2021	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Research Infrastructure Programs	001	2	3/13/2021	NON-COMPETING CONTINUATION	$74,232
														Subtotal = $987,743

Issue Date FY: 2020 ( Subtotal = $740,894 )
2020	2020	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Research Infrastructure Programs	001	1	4/29/2020	NEW	$185,155
2020	2020	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Research Infrastructure Programs	000	1	2/12/2020	NEW	$555,739
														Subtotal = $740,894

Grand Total All Awards = $3,197,111

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Developing second generation SCID pig models: filling the gaps to improve translation of therapeutics in regenerative medicine

Award Number: R24OD028748

ORGANIZATION: OFFICE OF THE DIRECTOR, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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