Oligonucleotide IMT504 Improves Glucose Metabolism and Controls Immune Cell Mediators in Female Diabetic NOD Mice IMT504, a Potential Therapy for Type 1 Diabetes

MARTÍNEZ ALLO, VERÓNICA C.; BORZONE, FRANCISCO R.; LIBERTUN, CARLOS; TOSCANO, MARTA A.; MASSIMINO, MILENA; GOMEZ BUSTILLO, SOFÍA; MONTANER, ALEJANDRO D.; LUX-LANTOS, VICTORIA A.; BIANCHI, STEFANIA; LAVIGNOLLE HEGUY, MARÍA DEL R.; CHASSEING, NORMA A.; RABINOVICH, GABRIEL A.; BIANCHI, MARÍA S.

Nucleic Acid Therapeutics

Mary Ann Liebert

Lugar: New York; Año: 2020

2159-3337

Type 1 diabetes occurs as a consequence of progressive autoimmune destruction of betacells. A potential treatment for this disease should address the immune attack on beta cellsas well as their preservation/regeneration. The objective of the current study was toelucidate whether the immunomodulatory synthetic oligonucleotide IMT504 was able toameliorate diabetes in NOD mice and to provide further understanding of its mechanism ofaction. We found that IMT504 restores glucose homeostasis in a diabetes mouse modelsimilar to human type 1 diabetes, by regulating expression of immune modulatory factorsand improving beta cell function. IMT504 treatment markedly improved fasting glycemia,insulinemia and HOMA-Beta cell index. Moreover, this treatment increased islet numberand decreased apoptosis, insulitis and CD45+ pancreas-infiltrating leukocytes. In a longterm treatment, we observed improvement of glucose metabolism up to 9 days after IMT504 cessation and increased survival after 15 days of the last IMT504 injection. We55 postulate that IL-12B (p40), possibly acting as a homodimer, and Galectin-3 (Gal-3) may56 function as mediators of this immunomodulatory action. Overall these results validate the57 therapeutic activity of IMT504 as a promising drug for type 1 diabetes and suggest possible58 downstream mediators of its immunomodulatory effect