Tu175 - Probiotic Delivery of Galectin-1: A New Therapeutic Strategy for Inflammatory Bowel Diseases

Luciano G. Morosi – Laboratorio de Glicomedicina, Instituto de Biología y Medicina Experimental-CONICET, Buenos Aires, Argentina.; Victor S. Blancato – Laboratorio de Fisiología y Genética de Bacterias Lácticas, Instituto de Biología Molecular y Celular de Rosario (IBR), Rosario, Argentina; Juan M. Pérez Sáez – Laboratorio de Glicomedicina, Instituto de Biología y Medicina Experimental-CONICET, Buenos Aires, Argentina.; Rosa Morales – Laboratorio de Glicomedicina, Instituto de Biología y Medicina Experimental-CONICET, Buenos Aires, Argentina.; Montana Manselle Cocco – Laboratorio de Glicomedicina, Instituto de Biología y Medicina Experimental-CONICET, Buenos Aires, Argentina.; Mora Massaro – Laboratorio de Glicómica Funcional y Molecular, Instituto de Biología y Medicina Experimental-CONICET, Buenos Aires, Argentina; Rodrigo Papa Gobbi – Instituto de Estudios Inmunológicos y Fisiopatológicos, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, La Plata, Argentina; Marta A. Toscano – Hospital Dr Arturo Oñativia, Salta, Argentina.; Christian Magni – Laboratorio de Fisiología y Genética de Bacterias Lácticas, Instituto de Biología Molecular y Celular de Rosario (IBR), Rosario, Argentina; Karina V. Mariño – Laboratorio de Glicómica Funcional y Molecular, Instituto de Biología y Medicina Experimental-CONICET, Buenos Aires, Argentina; Gabriel A. Rabinovich – 1. Laboratorio de Glicomedicina, Instituto de Biología y Medicina Experimental-CONICET, Buenos Aires, Argentina. 2. Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina

Abstract Text: Inflammatory bowel diseases (IBD) are chronic and progressive inflammatory conditions that severely affect quality of life. Although introduction of TNF-α-neutralizing monoclonal antibodies has revolutionized IBD therapy, a third of patients do not respond to this treatment. Thus, the search for new therapeutics to improve disease outcomes and quality of life remains a major area of interest. Recently, we reported dysregulation of the β-galactoside-binding protein galectin-1 (Gal1) and its glycosylated ligands in patients with IBD and validated its therapeutic potential in experimental colitis. This work encouraged us to find a selective delivery method of Gal1 through oral administration. We genetically engineered Lactococcus lactis (L. lactis) to deliver Gal1 as a new therapeutic approach for intestinal inflammation. We generated a novel construct for Gal1 expression in L. lactis, yielding higher amounts of bioactive human Gal1 as evidenced by Western-blot, ELISA and glycan-binding assay. Supernatants of Gal1-secreting L. lactis induced more rapid wound closure in human colon cells (p < 0.05), compared to L. lactis or Gal1. Using the 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced mouse model of colitis in Gal1-deficient (Lgals1-/-) mice, we demonstrated active delivery of Gal1 to the gut with daily intragastric administration of 1x109 CFU of Gal1-secreting L. lactis. Treatment with Gal1-secreting L. lactis significantly decreased weight-loss and macroscopic inflammation in these animals (p < 0.05). Additionally, WT mice show a significant decrease in local IFN-γ expression (p < 0.05). Thus, oral administration of genetically-modified L. lactis offers an effective targeted delivery system of human Gal1, as a novel potential therapeutic approach for IBD patients.