Plasmid-Encoded Proinsulin Preserves C-Peptide While Specifically Reducing Proinsulin-Specific CD8(+) T Cells in Type 1 Diabetes
Details
Publication Year 2013-06-26,Volume 5,Issue #191,Page 191ra82
Journal Title
SCIENCE TRANSLATIONAL MEDICINE
Publication Type
Journal Article
Abstract
In type 1 diabetes (T1D) an intense inflammatory response destroys beta cells in the pancreas, where insulin is produced and released. A therapy for T1D that reduces 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 adaptive immunity in T1D. We hypothesized that an engineered DNA plasmid encoding proinsulin (BHT-3021) would preserve beta cell function in T1D patients through reduction of insulin-specific T cells. We studied 80 subjects over 18 years of age who were diagnosed with T1D within 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 served as an exploratory measure of efficacy and safety. Islet-specific CD8(+) T cell frequencies were assessed with multimers of monomeric human leukocyte antigen class I molecules loaded with peptides containing pancreatic or unrelated antigens. No serious adverse events related to BHT-3021 occurred. C-peptide levels improved relative to placebo at all doses, most notably at 1 mg at 15 weeks (+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). 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.
Publisher
AMER ASSOC ADVANCEMENT SCIENCE
Keywords
INSULIN; AUTOANTIBODIES; EXPRESSION; TRIALS; ONSET
Research Division(s)
Molecular Medicine
Terms of Use/Rights Notice
Copyright © 2013, American Association for the Advancement of Science


Creation Date: 2013-06-26 12:00:00
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