Prevention and treatment of GI obstruction syndromes in cystic fibrosis

 描述(申请人提供)：囊性纤维化(CF)是一种遗传性疾病，由囊性纤维化跨膜传导调节因子(CFTR)基因的各种缺陷引起，该基因参与了氯离子和碳酸氢根离子在细胞膜上的运输。主要累及肺、肠和胰腺。CF病的进展最常与肺功能下降有关；然而，CFTR也影响包括胃肠道在内的许多器官的电解质运输，导致胰腺功能不全。 营养不良，胃肠动力显著降低，改变了粪便微生物区系。在胃肠道，CFTR功能的降低或丧失导致电解质组成异常和管腔脱水，导致粘液粘稠和胃肠道动力减弱，在肺部也观察到这一点。因此，胎粪性肠梗阻在13-17%的CF新生儿中被观察到，并导致显著的发病率，包括导致永久性残疾的大肠切除。远端肠梗阻综合征(DIOS)，以前被称为胎粪性肠梗阻(MI)，在年龄较大的儿童和成人中会引起类似的事件，并与严重的发病率和长时间的住院有关。目前的治疗方法是非特异性的，类似于用于非CF人群的治疗，但强度大大增加；这包括渗透性大便软化剂和补充刺激性泻药，但没有解决粘液和大便阻塞的根本原因。目前，没有一种治疗方法可以解决CF粘液潜在的粘连特性，这些粘液会导致嵌顿的粘液、粪便和相关的炎症，这是一个重大的未得到满足的医疗需求。这项建议测试了一种新的口服多糖疗法，具有肺黏液溶解活性和抗炎GI作用，用于治疗CF阻塞性疾病和相关的内源性炎症。胃肠道梗阻的预防和治疗都将在大鼠模型中进行测试。将评估炎症和胃肠道损伤的生物标记物以及与治疗相关的回肠和空肠中基因表达的变化，以更好地了解作用机制。这项原则证明研究将用于确定这种新疗法的疗效及其作为候选药物的发展潜力。

 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 13-17% 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.