Creating Insulin Producing Beta Cells That Resist Autoimmune Destruction

Engineering TET2-deficient beta cells that resist autoimmune attack to create replacement cell therapies for type 1 diabetes.
Completed Endocrine Diseases Type 1 Diabetes Animal Models Biological & Mechanistic Cytokine Signaling Experimental Platforms & Models Functional Genomics & CRISPR Immune Tolerance In Vitro Models Therapeutic Development Translational & Clinical

Funding Year: 2023

Project Overview

Type 1 diabetes occurs when the immune system gradually destroys insulin-producing beta cells through ongoing inflammation, including a harmful cycle in which damaged beta cells attract further immune attack. Recent research identified TET2 — a protein regulating gene activity and inflammation — as a key player in this process. Studies in animal models and human-derived beta cells show that TET2-deficient cells are more resistant to immune-mediated destruction. This project creates human beta cells without TET2 using CRISPR/Cas9, with the goal of producing replacement cells that resist future immune attacks. These engineered cells may be used alone or following a preconditioning regimen with teplizumab, and the work also identifies downstream targets — including BACH2, CHOP, ATF4, and caspases — for future immune therapies.

Impact & Innovation

Engineering beta cells that survive autoimmune attack.

 

By deleting TET2 in human stem cell-derived beta cells, this project demonstrates that inflammatory resistance can be built into replacement cells — offering a new path to durable cell therapy for type 1 diabetes.

  • Establishes TET2 deletion as a viable strategy for protecting beta cells from inflammatory mediator-induced killing, identifying BACH2, CHOP, ATF4, and caspases as downstream therapeutic targets
  • Generates IP through a provisional patent (U.S. Application No. 63/738,410) for methods to improve survival of human stem cell-derived pancreatic beta cells, filed December 2024
  • Advances the Consortium’s From Mechanistic Insight to Translation pillar by moving a mechanistic discovery in beta cell biology directly into engineered cell therapy development and IND-enabling preclinical studies
Research Approach

A framework designed for discovery

This project combines CRISPR-based gene editing, human stem cell biology, and preclinical immune challenge models to engineer TET2-deficient beta cells resistant to autoimmune destruction, and to identify the downstream pathways mediating that resistance. The work moves from cell engineering through functional validation and iPSC-based clinical preparation.


CRISPR/Cas9 deletion of TET2 in human embryonic stem cell-derived beta cells and iPSCs from T1D patients; in vitro inflammatory mediator-induced killing assays; ER stress pathway analysis to identify TET2-dependent protection mechanisms; human insulin secretion studies comparing WT and TET2KO cells following exposure to diabetes antigen-reactive CD8+ T cells; and iPSC preparation from T1D patients who were poor or robust responders to teplizumab.

Human embryonic stem cell-derived beta cells and human islets with TET2 deletion, iPSCs prepared from 6 T1D clinical trial participants, preclinical immune challenge datasets measuring resistance to inflammatory killing, ER stress pathway gene expression data, and human insulin secretion data from TET2KO vs. WT beta cells exposed to patient-derived CD8+ T cells.


Validation of TET2-deficient beta cells as functionally insulin-secreting and resistant to autoimmune destruction, with identification of targetable ER stress and inflammatory pathways. Replacement cells are designed for use alone or following teplizumab preconditioning, with a provisional patent filed and substantial follow-on funding secured to advance toward clinical application.

Investigators & Institutions

Powering the science

Principal Investigator

Kevan C. Herold, MD, Colton Consortium Member

C.N.H. Long Professor, Department of Immunobiology, Yale School of Medicine, Yale University

Colton Centers & Institutions

Colton Center for Autoimmunity at Yale University

Research Outputs

From insight to impact

Publications

Characteristics of autoantibody-positive individuals without high-risk HLA-DR4-DQ8 or HLA-DR3-DQ2 haplotypes

Diabetologia
Redondo, MJ; Cuthbertson, D; Steck, AK; Herold, KC; Oram, R; Atkinson, M; Brusko, TM; Parikh, HM; Krischer, JP; Onengut-Gumuscu, S; Rich, SS; Sosenko, JM; Type 1 Diabetes TrialNet Study Group December 2024
Adaptive ImmunityAutoantibodiesBiological & MechanisticDisease SubtypingEarly Disease DetectionExperimental Platforms & ModelsHuman CohortsHuman GeneticsTranslational & ClinicalEndocrine DiseasesType 1 DiabetesYale University

Teplizumab induces persistent changes in the antigen-specific repertoire in individuals at risk for type 1 diabetes

The Journal of Clinical Investigation
Lledó-Delgado, A; Preston-Hurlburt, P; Currie, S; Clark, P; Linsley, PS; Long, SA; Liu, C; Koroleva, G; Martins, AJ; Tsang, JS; Herold, KC August 2024
Adaptive ImmunityAutoantigensBiological & MechanisticClinical TrialsEarly Disease DetectionExperimental Platforms & ModelsHuman CohortsImmune ProfilingImmune TolerancePrecision MedicineT Cell BiologyTherapeutic DevelopmentTranslational & ClinicalEndocrine DiseasesType 1 DiabetesYale University

Trajectory of beta cell function and insulin clearance in stage 2 type 1 diabetes: natural history and response to teplizumab

Diabetologia
Galderisi, A; Sims, EK; Evans-Molina, C; Petrelli, A; Cuthbertson, D; Nathan, BM; Ismail, HM; Herold, KC; Moran, A November 2024
Adaptive ImmunityBiological & MechanisticBiomarker DiscoveryClinical TrialsDisease SubtypingEarly Disease DetectionExperimental Platforms & ModelsHuman CohortsTherapeutic DevelopmentTranslational & ClinicalEndocrine DiseasesType 1 DiabetesYale University

Additional Outputs

Grants funded from this project:

  • NIDDK: $1,316,678; Beatson Foundation: $267,025
  • Innovative T1D Treatment (JDRF): $250,000.

U.S. Provisional Application No. 63/738,410 — “Methods for improving survival of human stem cell derived pancreatic beta cells.” Filed 12/23/2024.