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Sci Transl Med. 2013 Jun 26;5(191):191ra82. doi: 10.1126/scitranslmed.3006103.

Plasmid-encoded proinsulin preserves C-peptide while specifically reducing proinsulin-specific CD8⁺ T cells in type 1 diabetes.

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Department for Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
Bayhill Therapeutics, Palo Alto, CA 94304, USA.
Foothill College, Los Altos, CA 94022, USA.
Barbara Davis Center for Childhood Diabetes, Aurora, CO 80045-6511, USA.
Division of Molecular Medicine, Walter and Eliza Hall Institute for Medical Research, Parkville, Victoria 3052, Australia.
Pacific Northwest Diabetes Research Institute and University of Washington, Seattle, WA 98122, USA.
Diabetes Center for Research, University of North Carolina, Chapel Hill, NC 27599, USA.
La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
Departments of Medicine and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
Tolerion Inc., 321 Dedalera Drive, Portola Valley, CA 94028, USA.
Contributed equally


In type 1 diabetes (T1D), there is an intense inflammatory response that destroys the β cells in the pancreatic islets of Langerhans, the site where insulin is produced and released. A therapy for T1D that targets the specific autoimmune response in this disease while leaving the remainder of the immune system intact, has long been sought. Proinsulin is a major target of the adaptive immune response in T1D. We hypothesized that an engineered DNA plasmid encoding proinsulin (BHT-3021) would preserve β cell function in T1D patients through reduction of insulin-specific CD8⁺ T cells. We studied 80 subjects over 18 years of age who were diagnosed with T1D within the past 5 years. Subjects were randomized 2:1 to receive intramuscular injections of BHT-3021 or BHT-placebo, weekly for 12 weeks, and then monitored for safety and immune responses in a blinded fashion. Four dose levels of BHT-3021 were evaluated: 0.3, 1.0, 3.0, and 6.0 mg. C-peptide was used both as an exploratory efficacy measure and as a safety measure. Islet-specific CD8⁺ T cell frequencies were assessed with multimers of monomeric human leukocyte antigen class I molecules loaded with peptides from pancreatic and unrelated antigens. No serious adverse events related to BHT-3021 were observed. C-peptide levels improved relative to placebo at all doses, at 1 mg at the 15-week time point (+19.5% BHT-3021 versus -8.8% BHT-placebo, P < 0.026). Proinsulin-reactive CD8⁺ T cells, but not T cells against unrelated islet or foreign molecules, declined in the BHT-3021 arm (P < 0.006). No significant changes were noted in interferon-γ, interleukin-4 (IL-4), or IL-10 production in CD4 T cells. Thus, we demonstrate that a plasmid encoding proinsulin reduces the frequency of CD8⁺ T cells reactive to proinsulin while preserving C-peptide over the course of dosing.

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