Project Abstracts - CMAD

Paula Alonso-Guallart, DVM, PhD, New York Stem Cell Foundation
Rick Monsma, PhD, New York Stem Cell Foundation
Mark Mamula, PhD, Yale School of Medicine
Richard Kibbey, MD, PhD, Yale School of Medicine

Start Date: December 15, 2025

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Abstract

Type 1 diabetes (T1D) is an autoimmune disease with a metabolic outcome. A number of agents can change the course of the disease when given to patients with new onset (Stage 3 T1D) and teplizumab, the anti-CD3 mAb has been approved to delay the clinical diagnosis in patients at risk, prior to the clinical diagnosis. Two clear unmet needs have emerged from the clinical trial experience. First, the successful immunologic treatments do not last indefinitely and do not restore normal β cell function. Second not all patients respond to treatments. In this proposal, we plan to study the features of β cells between clinical cohorts that show different rates of progression to clinical T1D and in response to immune therapy (i.e. teplizumab) in the successful TN10 prevention trial. New York Stem Cell Foundation (NYSCF) Research Institute has developed robust, high- throughput robotic cell culture systems that have successfully been applied to induced pluripotent stem cells (iPSCs) reprogramming and differentiation into pancreatic organoids. Importantly, these procedures minimize technical variation, allowing the detection of complex, subtle disease phenotypes and responses to perturbation. Our overarching hypothesis is that there are β cell intrinsic features that determine the effects of immune mediators, progression of T1D and responses to therapies. Our overall goal is to identify the β cell intrinsic features that determine progression of T1D, their interactions with immune cells, and the responses to therapies. In the UG3, Phase 1 part of this program, we will characterize and analyze pancreatic organoids from 16 existing iPSCs (10 from patients with T1D and 6 healthy controls) and reprogram iPSCs and develop pancreatic organoids from 20 additional patients. We will also prepare autologous islet autoantigen reactive CD8+ T cell lines from the iPSC donors that will be used in responses with the organoids. We will validate our models for detection of β cell killing in vitro and in vivo and obtain preliminary data on the differences between the cohorts and with primary islets which we can determine our statistical power for studies in Phase 2. In the Phase 2 UH3 program, we will analyze and compare the responses of the islet organoids between cohorts and to primary islets including a detailed analysis of metabolic function. We will determine the changes in the islet organoids when they are exposed to inflammatory mediators and specifically analyze protein modifications and development of neoantigens that may be targeted by antigen reactive CD8+ T cells. We will test whether deletion of TET2 in the islet organoids, that we have shown is required for inflammatory responses of β cells, will prevent immune mediated killing of the organoids. Finally, we will use the NYSCF automated platform to screen molecules for their ability to prevent organoid damage and death from inflammatory mediators. Understanding mechanisms of β cell failures in this context will direct therapies to prolong efficacy of immune treatments to arrest autoimmunity, and permit restoration of metabolic function for individual patients.