Phase I Clinical Trial of Islet Antigen–Specific Plasmid Coexpressing Tolerogenic Proteins Demonstrates Safety in Adults With Type 1 Diabetes
Year: 2026
Type: article
Abstract: There is significant interest in antigen-specific approaches to delaying type 1 diabetes in preclinical stages and supporting tolerance after diagnosis. We conducted a phase I trial of a nonintegrating DNA plasmid constructed to secrete the type 1 diabetes antigen preproinsulin (PPI) and the immune modulatory cytokines transforming growth factor-β1 (TGF-β1), interleukin-10 (IL-10), and IL-2. In this placebo-controlled, double-masked study of 47 adults with stage 3 type 1 diabetes, we showed that the drug is safe and well tolerated, with most reported adverse events (AEs) categorized as grade 1 and with no clinically significant difference in AEs among treatment groups. There were no untoward metabolic or immune effects. We found pharmacodynamic evidence of treatment, as demonstrated by a dose-dependent type 1 interferon (IFN) signature. Plasmid DNA, representing a pharmocokinetic measure, was detected in the two highest dosing groups. We did not find global or antigen-specific immune cell changes following treatment with a DNA plasmid expressing PPI, IL-2, IL-10, and TGF-β1, and we did not detect immune changes driven by IL-2, IL-10, or TGF-β1. Our results support further trials of this novel tolerizing antigen construct. ARTICLE HIGHLIGHTS: Antigen-specific therapy is needed to induce tolerance in type 1 diabetes at early disease stages or in combination with immunotherapy. We conducted a phase I trial in type 1 diabetes of a novel plasmid construct expressing the islet antigen preproinsulin (PPI) and immunomodulatory cytokines transforming growth factor-β1 (TGF-β1), interleukin-10 (IL-10), and IL-2. The therapy was safe and well tolerated. Dose-dependent changes in DNA plasmid levels and type 1 interferon signatures were detected; however, global and antigen-specific immune changes to PPI, IL-2, IL-10, or TGF-β1 were not observed. Further trials are needed to assess efficacy.
Source: Diabetes
DOI: 10.2337/db25-0777
Authors: Carla J. Greenbaum, S. Alice Long, Stephen E. Gitelman, Jason L. Gaglia, Mark Daniels, Todd M. Brusko, Sandra Lord, Brian N. Bundy, Jeffrey P. Krischer, Michael J. Haller, Andrea K. Steck, Linda A. DiMeglio, Carmella Evans-Molina, Antoinette Moran, Priya Prahalad, Darrell M. Wilson, William E. Russell, Jennifer L. Sherr, Philip Raskin, Mark A. Clements, Wayne V. Moore, Ingrid Libman, Karsten Wassermann, Matthias von Herrath, Regine Bergholdt, Hanne Hastrup, Sarah E. Kobernat, Anna M. Kus, Lin Wei Tung, Robin S. Goland, Kevan C. Herold, Type 1 Diabetes TrialNet Study Group*
Institutions: Benaroya Research Institute, University of California, San Francisco, Joslin Diabetes Center, Harvard University, Children's Hospital of Orange County, University of Florida, University of South Florida, University of Colorado Anschutz, University of Colorado Denver, Indiana University Indianapolis, Indiana University, University of Minnesota, Stanford Medicine, Stanford University, Vanderbilt University, Vanderbilt University Medical Center, Yale University, The University of Texas Southwestern Medical Center, Children's Mercy Hospital, University of Missouri–Kansas City, University of Pittsburgh, Novo Nordisk (Denmark), Columbia University
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Awards: G1058663374, G1335891746, G1667355478, Type 1 Diabetes TrialNet: Clinical Centers, TrialNet: University of Florida Clinical Center and Network, G180872007, Type 1 Diabetes-A Proposal for Prevention & Intervention, G2078056140, Chicagoland Diabetes TrialNet Clinical Center, G2325591987, G2579296307, G3255476064, G3345811275, Continuation of UCSF as a Clinical Center for TrialNet, G3998258134, Prediction and Prevention of Type 1 Diabetes (TrialNet), Northwest Clinical Center for Type 1 Diabetes - TrialNet, G4552347576, G457535738, G491993124, Type 1 Diabetes TrialNet: Clinical Center at Berrie Center, Columbia University, TrialNet at Stanford University, G6173851391, G695377212, G701880105, TrialNet: Diabetes Type 1 Prevention
OpenAlex ID: W7125400932