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Combined engineering of human stem cell-derived beta cells and regulatory T cells to treat type 1 diabetes

Award Number: R01AI201496
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/17/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Combined engineering of human stem cell-derived beta cells and regulatory T cells to treat type 1 diabetes - PROJECT SUMMARY/ABSTRACT Transplantation of cadaveric pancreatic islets can restore exogenous insulin independence to patients with type 1 diabetes (T1D), a chronic autoimmune disease in which insulin-producing pancreatic beta cells are recognized and destroyed by the immune system. Yet, this approach is limited by islet donor scarcity, the need for toxic systemic immunosuppressive drug regimens, and declining graft function post transplantation. Human pluripotent stem cell (hPSC) derived beta cells (sBCs) provide an unlimited source of replacement beta cells but, like cadaveric islets, they are vulnerable to allogeneic and autoimmune rejection by the recipient’s immune system. New strategies are thus urgently needed to achieve safe and durable immune protection of transplanted beta cells. Regulatory T cells (Tregs) are a specialized subset of immune cells dedicated to suppressing immune responses. We have developed a novel approach co-engineering hPSCs and Tregs. We created a unique synthetic, biologically inert cell surface ligand that can be stably expressed on sBCs. In parallel, we engineered Tregs to express a new chimeric antigen receptor (CAR), a synthetic immune receptor comprising an antigen- binding domain and a T-cell signaling domain, specific for this unique ligand. In Aim 1, we will thoroughly characterize synthetic ligand-expressing sBCs. In Aim 2, we will test ligand-specific CAR Treg-mediated suppression of multiple immune subsets in the presence of ligand-expressing sBCs in vitro. In Aim 3, we will evaluate and genetically dissect the suppressive function of ligand-specific CAR Tregs in vivo using advanced humanized mouse models of T1D that incorporate ligand-expressing sBCs and various human immune effector immune cell populations, including alloreactive and autoreactive T cells. The proposed studies will pioneer the use of co-engineered Tregs and sBCs to achieve localized, durable graft immune protection. This synthetic ligand-CAR system is highly innovative because it creates a unique, tolerogenic recognition module that can be applied broadly to other stem cell-derived grafts and be used instead of or in synergy with methodologies involving editing immune genes in stem cells. This work has the potential to transform T1D therapy by enabling safe, long-term beta cell replacement without systemic immunosuppression, to shed light on CAR Treg mechanisms of action, and to establish a broadly applicable paradigm for regenerative medicine.


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 = $640,131 )
2026	2026	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Allergy and Infectious Diseases Research	000	1	9/17/2026	NEW	$640,131
														Subtotal = $640,131

Grand Total All Awards = $640,131

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Combined engineering of human stem cell-derived beta cells and regulatory T cells to treat type 1 diabetes

Award Number: R01AI201496

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/17/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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