Prevention and treatment of GI obstruction syndromes in cystic fibrosis

DESCRIPTION provided by applicant Cystic fibrosis CF is a genetic disease resulting from a variety of defects of the cystic fibrosis transmembrane conductance regulator CFTR gene that is involved in the transport of chloride and bicarbonate ions across the cell membrane CF mostly affects the lungs intestines and pancreas The progression of the CF disease is most commonly associated with decline in pulmonary function however the CFTR also affects electrolyte transport in many organs including the GI tract resulting in pancreatic insufficiency nutritional malabsorption and significant reductions in gastrointestinal GI motility altering te fecal microbiota In the GI tract the reduction or loss of CFTR function results in abnormal electrolyte composition and dehydration of the lumen resulting in thick adherent mucus and reduced GI motility as also observed in the lungs Consequently meconium ileus is observed in of CF newborns and causes significant morbidity including large resections of bowel that cause permanent disability Distal intestinal obstructive syndrome DIOS formerly called meconium ileus MI equivalent causes similar events in older children and adults and is associated with severe morbidity and prolonged hospitalizations Current treatments are non specific and similar to that used for the non CF population but with greatly increased intensity this includes osmotic stool softeners and supplementation with stimulant laxatives but do not address the underlying cause of mucus and stool obstruction Currently no current treatments are intended to address the underlying adhesive properties of CF mucus that cause impacted mucus stool and associated inflammation representing a significant unmet medical need This proposal tests a novel orally administered polysaccharide therapeutic with demonstrated pulmonary mucolytic activity and anti inflammatory GI action to treat CF obstructive disorders and associated intrinsic inflammation Both prophylaxis and treatment of GI obstruction will be tested in rat models Biomarkers of inflammation and GI damage will be assessed along with gene expression changes in the ileum and jejunum associated with treatment in order to better understand mechanisms of action This proof of principle study will be used to determine the efficacy of this new therapeutic and its potential for advancement as a drug candidate PUBLIC HEALTH RELEVANCE Cystic fibrosis CF is a genetic disease resulting defects of the cystic fibrosis transmembrane conductance regulator CFTR gene that is involved in the transport of chloride and bicarbonate ions across the cell membrane In the GI tract the reduction or loss of CFTR function results in abnormal electrolyte composition and dehydration of the lumen resulting in thick adherent mucus and reduced GI motility meconium ileus distal intestinal obstructive syndrome DIOS and is associated with severe morbidity and prolonged hospitalizations This proposal tests a novel orally administered polysaccharide therapeutic with demonstrated pulmonary mucolytic activity and anti inflammatory GI action to treat CF obstructive disorders and associated intrinsic inflammation in animal models