Optimization of recombinant probiotics for oral delivery of ACE2/Ang-(1-7

PROJECT SUMMARYABSTRACT Cardio pulmonary diseases are the leading cause of morbidity and mortality worldwideDespite recent advances in drug therapy and improvements in patient carecardio pulmonary diseases remains a fatal diseaseAngiotensin converting enzymeACEand angiotensinAngprotective axis of the renin angiotensin systemRAShas emerged as highly effective in producing beneficial effects on metabolicimmune and cardiopulmonary dysfunctions by blocking apoptosisfibrosisoxidative stressand inflammationRecent findings from our team and others provide unequivocal support that the ACEAngaxis plays a protective role against cardio pulmonary diseasesHoweverthe biggest impediment to translate this fundamental knowledge into clinical applications for management and treatment of these diseases is large scale production of high quality ACEand Angwith sufficient target tissue bioavailabilityMedosome BiotecLLC and its research partners at the University of Florida have identified a solution that offers tremendous commercial potential for treating cardio pulmonary diseasesThe team hypothesizes that recombinant probiotics based oral delivery of protein therapeutics represent an innovativemore efficient and cost effective strategy to enhance this protective axis at both circulating and target tissues for clinical applicationPreliminary data from our UF team members have demonstrated thatACEand Angcan be efficiently expressed and secreted from the probiotic bacteriumLactobacillus paracaseiand reach therapeutic levels in the circulation and target tissues using plasmid vectors that contain antibiotics resistant gene as selection markeroral administration of Lactobacillus paracasei expressing Angprevented monocrotalineMCTinduced pulmonary hypertensiongut pathophysiology and dysbiosisThe overall objective of this project is to construct and characterize antibioticsmarker free vectors for expression of ACEand Angin probioticsand confirm their efficacy in animal models of pulmonary hypertensionThe completion of these studies will position us to initiate Phase II studies in which we will conduct preclinical experiments that will enable us to submit a completed IND application to the FDA Center for BiologicsIn additionwe will build capacity for producing GMP grade material for the clinical trials PROJECT NARRATIVE Cardio pulmonary diseases are the leading cause of morbidity and mortality worldwideACEAngthe protective axis of the renin angiotensin systemhas emerged as a potent protective pathway by blocking oxidative stressinflammationand improving metabolicimmune and cardiovascular functionsHowever it is challenging to enhance this protective axis with sufficient target tissue bioavailability for scale up clinical application using conventional approachThis project develops an innovativemore efficient and cost effective technology using recombinant probiotics to enhancing this protective axis for treating metabolic and cardiopulmonary diseases