An international team of scientists today reports that they have successfully short-circuited immune responses that attack pancreatic insulin-producing cells, presenting a novel approach to treating type 1 diabetes (T1D). Their “reverse vaccine,” a plasmid engineered to turn off gene sequences that stimulate the immune system and switch on gene sequences that suppress it, could help T1D patients preserve these cells and help treat this autoimmune disease, the scientists suggest today in Science Translational Medicine.

T1D is an autoimmune disease in which the immune system attacks insulin-producing pancreatic beta cells and requires lifelong treatment with multiple daily insulin injections. This autoimmune response is in part mediated by CD8+ T cells against various islet cell antigens including preproinsulin (PPI), the molecular precursor to insulin and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP). These cells have been detected in the blood and in the pancreatic islets of individuals with T1D.

Lead author Bart O. Roep, M.D., Ph.D., of the University of Leiden along with his colleagues elsewhere noted that therapy for T1D that targets the specific autoimmune response in this disease while leaving the remainder of the immune system intact, has long been a goal of diabetes researchers.

For this study, the investigators said they attempted to modulate, in an antigen-specific manner, the adaptive immune response to proinsulin with an engineered DNA vaccine encoding proinsulin. The vaccine was engineered to reduce the immunogenicity of the encoded proinsulin by substituting CpG hexameric motifs, which stimulate the innate immune response, with GpG hexameric nucleotide sequences, known to modulate innate immunity.

The investigators tested the effects of the vaccine in 80 subjects over 18 years of age who had been diagnosed with T1D within the past five years. Patients were randomized 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.

Results of the study demonstrated that an engineered plasmid that expresses proinsulin could preserve B cell function in T1D patients. In patients, C-peptide, a marker of b cell function, rose, and as the peptide increased, a deletion of CD8+T cells reactive to proinsulin, with no effect on other antigen-specific T cell responses, also occurred. No serious side effects among patients treated with the DNA vaccine were observed, the researchers report.

The findings indicate that by targeting the root cause of T1D, reverse vaccination could potentially change the course of events that lead to severe disease, and that the approach may also be helpful for treating other autoimmune diseases.

“This is the first demonstration of a DNA vaccine targeting type 1 diabetes in humans,” said Richard Insel, M.D., chief scientific officer of JDRF, formerly known as the Juvenile Diabetes Research Foundation.

“Plasmid-encoded proinsulin preserves C-peptide while specifically reducing proinsulin-specific CD8+ T cells in type 1 diabetes” was published online in Science Translational Medicine June 26.

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