Preclinical evaluation of a precision medicine approach to DNA vaccination in type 1 diabetes

Jorge Postigo-Fernandez, Rebuma Firdessa-Fite, Rémi J. Creusot

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Antigen-specific immunotherapy involves the delivery of self-antigens as proteins or peptides (or using nucleic acids encoding them) to reestablish tolerance. The Endotope platform supports the optimal presentation of endogenously expressed epitopes on appropriate major histocompatibility complex (MHC) class I and II molecules. Using specific epitopes that are disease-relevant (including neoepitopes and mimotopes) and restricted to the subject's MHC haplotypes provides a more focused and tailored way of targeting autoreactive T cells. We evaluated the efficacy of an Endotope DNA vaccine tailored to the nonobese diabetic (NOD) mouse in parallel to one expressing the Proinsulin protein, a central autoantigen in NOD mice, and assessed the influence of several parameters (e.g., route, dosing frequency, disease stage) on diabetes prevention. Secretion of encoded peptides and intradermal delivery of DNA offered more effective disease prevention. Long-term weekly treatments were needed to achieve protection that can persist after discontinuation, likely mediated by regulatory T cells induced by at least one epitope. Although epitopes were presented for at least 2 wk, weekly treatments were needed, at least initially, to achieve significant protection. While Endotope and Proinsulin DNA vaccines were effective at both the prediabetic normoglycemic and dysglycemic stages of disease, Proinsulin provided better protection in the latter stage, particularly in animals with slower progression of disease, and Endotope limited insulitis the most in the earlier stage. Thus, our data support the possibility of applying a precision medicine approach based on tailored epitopes for the treatment of tissue-specific autoimmune diseases with DNA vaccines.

Original languageEnglish (US)
Article number2110987119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number15
DOIs
StatePublished - Apr 12 2022
Externally publishedYes

Keywords

  • autoimmune diabetes
  • DNA vaccine
  • epitope
  • precision medicine
  • tolerance

ASJC Scopus subject areas

  • General

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