Oligonucleotide IMT504 improves glucose metabolism and controls immune cell mediators in female diabetic NOD mice

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

Nucleic Acid Therapeutics

Mary Ann Liebert Inc.

Lugar: New Rochelle, N.Y.; Año: 2020

2159-3337

Type 1 diabetes occurs as a consequence of progressive autoimmune destruction of beta 44 cells. A potential treatment for this disease should address the immune attack on beta cells as well as their preservation/regeneration. The objective of the current study was to elucidate whether the immunomodulatory synthetic oligonucleotide IMT504 was able to ameliorate diabetes in NOD mice and to provide further understanding of its mechanism of action. We found that IMT504 restores glucose homeostasis in a diabetes mouse model similar to human type 1 diabetes, by regulating expression of immune modulatory factors and improving beta cell function. IMT504 treatment markedly improved fasting glycemia, insulinemia and HOMA-Beta cell index. Moreover, this treatment increased islet number and decreased apoptosis, insulitis and CD45+ pancreas-infiltrating leukocytes. In a long- term 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. We postulate that IL-12B (p40), possibly acting as a homodimer, and Galectin-3 (Gal-3) may function as mediators of this immunomodulatory action. Overall these results validate the therapeutic activity of IMT504 as a promising drug for type 1 diabetes and suggest possible downstream mediators of its immunomodulatory effect.