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Functional Validation of Gene Modifications that Protect Beta Cells against Autoimmunity Identified by Genome-Wide CRISPR Cas9 Screening

Award Number: R01DK120445
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: 09/30/2018
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Functional Validation of Gene Modifications that Protect Beta Cells against Autoimmunity Identified by Genome-Wide CRISPR Cas9 Screening - PROJECT SUMMARY Type 1 diabetes (T1D) is caused by the immune destruction of insulin producing cells in the pancreas. The disease cannot be prevented, and the only treatment available is a life-long use of insulin injected multiple times a day. Insulin-producing beta cells can now be generated from pluripotent stem cells in the laboratory. This recent achievement has raised the prospect of restoring insulin production in patients by beta cell transplantation. However, the autoimmunity underlying T1D is long-lasting and will destroy new beta cells if they are transplanted without immunosuppression. A new therapy that protects beta cells is urgently needed not only enable curative beta cell replacement in patients but also to prevent diabetes in individuals at risk of developing the disease. To discover genetic targets for such a therapy, we performed a genome-wide search using CRIPSR-Cas9 genome editing in a mouse model for T1D. This broad unbiased search identified the gene Renalase (RNLS). Significantly, RNLS had previously been associated with the overall risk and the age- of-onset of T1D by human genome-wide association studies (GWAS), suggesting a role for RNLS in diabetes pathogenesis. We went on to confirm that deleting RNLS protected mouse beta cells against cellular stress and autoimmunity. We corroborated the protective effect of RNLS deletion in human stem cell-derived beta cells. Based on these findings, we hypothesized that a small molecule inhibitor of RNLS would also protect. Using structure-based molecular modeling, we identified the FDA-approved drug pargyline as a potential RNLS inhibitor. We showed that pargyline treatment replicated the protective effects of RNLS deletion, making this drug a potential candidate for a preventive treatment for T1D. Now, we aim to better understand how RNLS deficiency protects beta cells against cellular stress and autoimmunity. Further, we aim to more extensively test the therapeutic potential of pargyline. To these ends, we will pursue three Specific Aims. First, we will evaluate metabolic plasticity as a possible mechanistic basis for the protection of RNLS deficient cells. Second, we will quantify and delineate the immunogenicity of Rnls deficient beta cells in vitro and in mouse models for T1D. Third, we will evaluate the therapeutic utility of pargyline as a mimic of Rnls deletion, both at the cellular level and in the context of autoimmune diabetes in mice. Completing the first two Aims will help explain the mechanism by which RNLS modifies beta cell vulnerability and the risk of type 1 diabetes. The third Aim will support the translation of our discoveries into a clinical application by testing the therapeutic value of drug we identified as a RNLS inhibitor. Our research team is composed of experts in immunology, beta cell biology and stem cell differentiation. We are ideally positioned to explore the role of RNLS in T1D from perspectives that range from cellular biology to systemic autoimmunity, with the prospect of improving our understanding of disease pathology and developing a preventive drug. Our research will utilize both a well characterized mouse model for T1D and human beta cells to ascertain the relevance of our findings for human disease.


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 = $0 )
2025	2024	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	7/1/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $405,600 )
2024	2024	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	2/28/2024	NON-COMPETING CONTINUATION	$380,250
2024	2024	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	5/3/2024	NON-COMPETING CONTINUATION	$25,350
														Subtotal = $405,600

Issue Date FY: 2023 ( Subtotal = $422,500 )
2023	2023	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	2/17/2023	NON-COMPETING CONTINUATION	$422,500
2023	2022	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	12/6/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $422,500

Issue Date FY: 2022 ( Subtotal = $422,500 )
2022	2022	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/18/2022	NON-COMPETING CONTINUATION	$380,250
2022	2022	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	4/6/2022	NON-COMPETING CONTINUATION	$42,250
														Subtotal = $422,500

Issue Date FY: 2021 ( Subtotal = $422,500 )
2021	2021	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	3/11/2021	COMPETING CONTINUATION	$422,500
2021	2019	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	9/1/2021	NON-COMPETING CONTINUATION	$0
2021	2019	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/10/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $422,500

Issue Date FY: 2019 ( Subtotal = $504,614 )
2019	2019	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	7/23/2019	NON-COMPETING CONTINUATION	$491,884
2019	2019	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/1/2019	SUPPLEMENT FOR EXPANSION	$12,730
														Subtotal = $504,614

Issue Date FY: 2018 ( Subtotal = $420,944 )
2018	2018	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/18/2018	NEW	$420,944
														Subtotal = $420,944

Grand Total All Awards = $2,598,658

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Functional Validation of Gene Modifications that Protect Beta Cells against Autoimmunity Identified by Genome-Wide CRISPR Cas9 Screening

Award Number: R01DK120445

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: 09/30/2018

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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