Design, Synthesis, and Biological Evaluation of Novel Cyclic Adenosine-Inosine Monophosphate (cAIMP) Analogs That Activate Stimulator of Interferon Genes (STING).

We describe novel STING-activating cyclic dinucleotides whose constituent nucleosides are adenosine and inosine and that vary by ribose substitution, internucleotide linkage position, and phosphate modification. In mammalian cells in vitro, some of these cAIMP analogs induce greater STING-dependent IRF and NF-κB pathway signaling than do the reference agonists for murine (DMXAA) or human (2',3'-cGAMP) STING. In human blood ex vivo, they induce type I interferons (IFNs) and proinflammatory cytokines: for the former, 3',3'-cAIMP (9; EC50 of 6.4 µM) and analogs 52-56 (EC50 of 0.4-4.7 µM), which contain one or two 2'-fluoro-2'-deoxyriboses and/or bis-phosphorothioate linkages, are more potent than 2',3'-cGAMP (EC50 of 19.6 µM). Interestingly, 9 induces type I IFNs more strongly than do its linkage isomers 2',3'-cAIMP (10), 3',2'-cAIMP (23), and 2',2'-cAIMP (27). Lastly, some of the cAIMP analogs are more resistant than 2',3'-cGAMP to enzymatic cleavage in vitro. We hope to exploit our findings to develop STING-targeted immunotherapies.

Cell-based therapy for heart failure in rat: double thoracotomy for myocardial infarction and epicardial implantation of cells and biomatrix.

Cardiac cell therapy has gained increasing interest and implantation of biomaterials associated with cells has become a major issue to optimize myocardial cell delivery. Rodent model of myocardial infarction (MI) consisting of Left Anterior Descending Artery (LAD) ligation has commonly been performed via a thoracotomy; a second open-heart surgery via a sternotomy has traditionally been performed for epicardial application of the treatment. Since the description of LAD ligation model, post-surgery mortality rate has dropped from 35-13%, however the second surgery has remained critical. In order to improve post-surgery recovery and reduce pain and infection, minimally invasive surgical procedures are presented. Two thoracotomies were performed, the initial one for LAD ligation and the second one for treatment epicardial administration. Biografts consisting of cells associated with solid or gel type matrices were applied onto the infarcted area. LAD ligation resulted in loss of heart function as confirmed by echocardiography performed after 2 and 6 weeks. Goldner trichrome staining performed on heart sections confirmed transmural scar formation. First and second surgeries resulted in less that 10% post-operative mortality.