Jamison Siebart
BME PhD Proposal Presentation
Date: 2026-04-01
Time: 3-5 PM
Location / Meeting Link: Suddath Seminar Room 1128; https://emory.zoom.us/j/97689421128
Committee Members:
Gabriel A. Kwong, PhD (Advisor); Andrés J. García, PhD; Leslie Chan, PhD; Marian Ackun-Farmmer, PhD; Madhav Dhodapkar, MBBS
Title: Antigen-specific T cell immunotherapy for type 1 diabetes by in vivo mRNA delivery
Abstract:
Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease in which autoreactive CD4 and CD8 T cells destroy insulin-producing pancreatic β cells, resulting in lifelong insulin dependence with no available cure. Current disease-modifying strategies rely on broad immunosuppression or pan-T cell modulation, which reduce autoreactive T cell activity but compromise global immune competence, increasing susceptibility to infection and failing to achieve durable remission. Recent advances in in vivo cell engineering, which enable the direct delivery of therapeutic transgenes into cells within the body, offer a promising alternative by enabling genetic modification of immune cells without ex vivo manipulation. Among available delivery platforms, lipid nanoparticles (LNPs) are particularly attractive due to their favorable safety profile, transient mRNA expression, and suitability for repeated dosing. While promising, LNPs currently under clinical development for T cell engineering rely on broadly expressed surface markers to target the entire circulating T cell repertoire, lacking the specificity required to selectively manipulate the rare diabetogenic clones that drive T1D pathology. This highlights the need for a delivery platform capable of targeting disease-relevant T cell populations with clonotype-level precision while preserving the broader immune repertoire. In this thesis proposal, we will develop LNPs functionalized with peptide–major histocompatibility complex (pMHC) class I and class II molecules, termed antigen-presenting nanoparticles (APNs), to enable in vivo mRNA delivery to antigen (Ag)-specific CD8 and CD4 T cells, respectively. APNs leverage the natural specificity of the T cell receptor (TCR)–pMHC interaction to selectively engage and transfect T cells of a defined antigen specificity. This strategy is expected to enable delivery of genetic payloads to rare disease-relevant T cell populations while minimizing broad perturbation of the overall T cell repertoire. We will first establish MHC class I APNs as a strategy for mRNA delivery to autoreactive CD8 T cells by coating LNPs with pMHC molecules recognized by diabetogenic CD8 T cells. We will then load the MHC class I APN with proapoptotic mRNA for selective depletion of autoreactive T cells to prevent hyperglycemia in a murine model of T1D (Aim 1). Building on this platform, we will extend APN technology to enable mRNA delivery to Ag-specific CD4 T cells through functionalization of LNPs with MHC class II molecules. We will first establish the ability of MHC class II APNs to deliver reporter mRNA constructs to Ag-specific CD4 T cells in models using TCR-transgenic murine CD4 T cells. We will then assess the efficacy of MHC class II APNs to therapeutically reprogram autoreactive CD4 T cells in murine models of autoimmune diabetes through delivery of immunosuppressive mRNA cargos (Aim 2). Successful completion of these studies will establish APNs as a platform for in vivo engineering of Ag-specific T cell immunotherapy for type 1 diabetes.
