# Engineering islet-like organoids from gastric stem cells for T1D cell replacement therapy

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $598,532

## Abstract

PROJECT SUMMARY
Islet transplantation offers a potential cure for Type 1 diabetes (T1D). Wide adoption of a cell therapy
requires abundant islet supplies and effective immune protection without long-term systemic immune
suppression. My laboratory and others showed that it was feasible to derive insulin-secreting cells
from renewable and abundant gastrointestinal (GI) stem cells. However, it has not been possible to
mass-produce islet-like organoids from human GI tissues for detailed assessment of their
translational potential.
In preliminary studies, we established methods to culture human gastric stem cells (hGSCs) from
biopsy samples and expanded them to billions. The hGSCs were engineered for transient activation
of NGN3 and stable expression of PDX1 and MAFA (collectively referred to as NPM factors), leading
to formation of thousands of GINS (Gastric Insulin Secreting) organoids. GINS organoids acquired
glucose-stimulated-insulin-secretion (GSIS) within 10 days, and upon transplantation, rapidly
reversed diabetes in mice and maintained normoglycemia for over 3 months, with no tumor
formation. Human GINS organoids thus have favorable attributes as a potential cell product for T1D
treatment with a scalable derivation method.
GINS organoids contain 25-30% of cells that closely resemble pancreatic Beta-cells. In this project, we
will evaluate the hypothesis that clonal hGSC lines yielding a higher percentage of Beta-like cells can
be readily identified from donor tissues. We will develop a standard derivation protocol using genetic
knockin of NPM and clonal selection with the aim to consistently produce highly functional GINS
grafts from donors. GINS cells lack key autoantigens and may be naturally less immunogenic than
islet Beta-cells. We will confer further autoimmune protection by constitutive expression of two potent
immune regulators PD-L1 an CD47. Normal and immune-evasive organoids will be evaluated in vitro
and in vivo with a panel of antigen-specific cytotoxic CD8 T cells, the main effector of Beta-cell demise
in T1D. Together, these studies will create a technology for reliable production of autologous GINS
grafts with strong autoimmune protection, suitable for long-term glycemic control without immune
isolation or suppression.

## Key facts

- **NIH application ID:** 10897183
- **Project number:** 5R01DK133701-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Shahin Rafii
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $598,532
- **Award type:** 5
- **Project period:** 2022-09-12 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10897183

## Citation

> US National Institutes of Health, RePORTER application 10897183, Engineering islet-like organoids from gastric stem cells for T1D cell replacement therapy (5R01DK133701-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10897183. Licensed CC0.

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