Immunomodulatory oligonucleotide IMT504 induces a marked recovery in a type I diabetes animal model

MONTANER A; BIANCHI MS; CALVO V; CHASSEING NA; LAGO N; LIBERTUN C; LUX LANTOS V

Río de Janeiro

Congreso; Advanced Technology & Treatments for Diabetes ? Latin America.; 2012

Sociedade Brasileira de Diabetes

Immunomodulatory oligonucleotide IMT504 induces a marked recovery in a type I diabetes animal model Montaner A1 , Bianchi S2, Calvo V2, Chasseing A2, Lago N3, Libertun C2,3, Lux-Lantos V2 (1). Fundación Pablo Cassará (ICT Milstein-CONICET). Buenos Aires, Argentina. (2). Instituto de Biología y Medicina Experimental (IByME-CONICET). Buenos Aires, Argentina. (3). Facultad de Medicina - Universidad de Buenos Aires. Buenos Aires, Argentina.   Immunomodulatory oligonucleotides (im-ODNs) are synthetic molecules that stimulate the innate immune system. We have identified a new ODN-family named PyNTTTTGT. Unlike other im-ODNs, its prototype IMT504 promotes tissue repair in experimental models of bone injury, peripheral nerve crush and pancreatic insult by stimulating progenitor cells. Here, we evaluated the effect of IMT504 on a type I diabetes model. Balb/C-mice were daily ip-injected with STZ (40mg/kg) for 5 days. Animals with glycaemia ³250 mg/dl were daily sc-injected with 20 doses of IMT504 (20mg/kg/dose) and followed for 60-days. A second group were treated as above, but killed after two consecutive decreases in glycaemia (2-5 doses). IMT504 induced a decline in blood glucose in 88% of treated-mice. At day-60 glycaemia (mg/dl) were: Control+Saline: 130±20, Control+IMT504: 115±28, STZ+Saline: 557±49, STZ+IMT504: 278±112 (p<0.01). Of note, IMT504 promoted a transient decrease in body weight. Moreover, IMT504-treated animals showed a partial recovery in pancreatic function as measured by GTT, HOMA-B and HOMA-IR. Supporting these findings, the number of islet per pancreatic area was enhanced in STZ+IMT504 vs. STZ+Saline. Also, there was a marked reduction of leukocyte infiltration in and around islets both at 5- or 60-days. Further, cytokine profile at early times showed an increase in IL6 and TNFα in IMT504-treated animals, a fact that could be associated with the release of immunomodulatory proteins IDO and TSG-6  in islets, at the time of progenitor markers expression. Preclinical assays have demonstrated that IMT504 is a very safe drug. Taken together, these results warrant further studies in the route to clinical application.         Saladillo 2468 (C1440FFX), Ciudad de Buenos Aires, Argentina. e-mail: amontaner@fundacioncassara.org.ar