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

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

Nucleic Acid Therapeutics

Mary Ann Liebert

Lugar: New York; Año: 2021 vol. 31 p. 155 - 171

2159-3337

Type 1 diabetes occurs as a consequence of progressive autoimmune destruction of beta cells. A potential treatment for this disease should address the immune attack on beta cells and their preservation/regeneration. The objective of this 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 homeostatic model assessment of beta cell function (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 interleukin (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.