Saturday, November 15, 2025 11/15/2025

Genome editing of human pancreatic islets to withstand ischemic injuries and promote immune evasion

Award Number: R01DK133645
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Genome editing of human pancreatic islets to withstand ischemic injuries and promote immune evasion - ABSTRACT In this proposal we apply somatic cell gene editing strategies to enhance pancreatic beta cell replacement therapies for type 1 diabetes (T1D). We have formed a team that combines expertise in beta cell biology, synthetic and systems biology, and islet transplant immunology to address key impediments for efficient immunosuppression-free transplantation of pancreatic islets. We propose two orthogonal yet complementary aims to address two critical challenges in islet transplantation - islet survival and immune rejection. Most of the transplanted islets die before revascularization can occur, which limits the efficacy of the therapy. We have shown hypoxia and nutrient deprivation during ischemia independently and synergistically kill transplanted islet cells. Aim 1 of this proposal addresses the hypothesis that peri-transplant death can be alleviated by deleting negative regulators of beta cell survival or by over-expression of positive regulators. We will take both targeted and unbiased approaches to test candidate regulators and to identify novel regulators of human islet survival. Our team has already performed high-throughput screens using RNAi in primary human islets using in vivo transplant survival as a readout. We are ready to apply our expertise to CRISPRi and cDNA screens of primary human islets. Previous clinical islet transplant experiences show that stronger immunosuppression is associated with higher rate of insulin independence after islet transplantation. The immune system deploys multiple redundant mechanisms to eliminate transplanted foreign tissue. This, combined with the fragility of the transplanted islets and heightened immune functions in T1D recipients, forms a formidable immunological barrier to beta cell replacement therapy. We hypothesize that multipronged approach of minimizing islet cell immunogenicity, neutralizing inflammation in the graft, and blocking cellular infiltrate will shield the islets from immune rejection without the need for systemic immunosuppression. In Aim2, we will test this hypothesis by gene edit human islets to ablate the expression of polymorphic human leukocyte antigens. We will test dominant strategies that block innate inflammatory cytokines TNF, IL-1 and type 1 and type 2 interferons. We will also target adaptive immune cells by blocking their trafficking, activation and effector function. Successful confirmation of our hypotheses will provide proof-of-principle data to support efforts of clinical translation as next steps. We envision that these strategies may be applied to primary human islets, stem cell-derived beta cells, and even xenogeneic islets. While these CRISPR modalities are powerful research tools for screens and proof- of-concept experiments in the laboratory, base editing and/or prime editing may be preferred embodiments in the clinical setting. Our end goal is to generate game-changing strategies to address these key impediments, with a vision towards clinical translation.


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 = $711,190 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/28/2025	NON-COMPETING CONTINUATION	$686,375
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	4	7/16/2025	SUPPLEMENT FOR EXPANSION	$24,815
2025	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	4/29/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	7/16/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $711,190

Issue Date FY: 2024 ( Subtotal = $733,365 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/7/2024	NON-COMPETING CONTINUATION	$658,920
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	8/21/2024	SUPPLEMENT FOR EXPANSION	$74,445
														Subtotal = $733,365

Issue Date FY: 2023 ( Subtotal = $686,375 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/15/2023	NON-COMPETING CONTINUATION	$686,375
														Subtotal = $686,375

Issue Date FY: 2022 ( Subtotal = $686,375 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/1/2022	NEW	$686,375
														Subtotal = $686,375

Grand Total All Awards = $2,817,305

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Genome editing of human pancreatic islets to withstand ischemic injuries and promote immune evasion

Award Number: R01DK133645

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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