Prevention and treatment of GI obstruction syndromes in cystic fibrosis

 描述（由申请人提供）：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，该基因参与氯离子和碳酸氢根离子跨细胞膜的转运。CF主要影响肺、肠和胰腺。CF疾病的进展最常与肺功能下降相关;然而，CFTR也影响许多器官（包括胃肠道）中的电解质转运，导致胰腺功能不全， 营养吸收不良和胃肠道（GI）运动显著减少，改变粪便微生物群。在胃肠道中，CFTR功能的降低或丧失导致电解质组成异常和管腔脱水，导致粘稠的粘附粘液和GI运动性降低，如在肺中也观察到的。因此，在13 - 17%的CF新生儿中观察到胎粪性肠梗阻，并导致显著的发病率，包括导致永久性残疾的大肠切除术。远端肠梗阻综合征（DIOS），以前称为胎粪性肠梗阻（MI），在年龄较大的儿童和成人中引起类似的事件，并与严重的发病率和长期住院有关。目前的治疗是非特异性的，与非CF人群相似，但强度大大增加;这包括渗透性粪便软化剂和补充刺激性泻药，但不能解决粘液和粪便阻塞的根本原因。目前，没有当前的治疗旨在解决CF粘液的潜在粘附特性，其导致粘液、粪便和相关炎症的影响，这代表了显著未满足的医疗需求。该提案测试了一种新型的口服多糖治疗剂，其具有经证实的肺粘液溶解活性和抗炎GI作用，以治疗CF阻塞性疾病和相关的内在炎症。将在大鼠模型中测试GI阻塞的预防和治疗。将沿着评估炎症和GI损伤的生物标志物以及与治疗相关的回肠和空肠中的基因表达变化，以更好地理解作用机制。这项原理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.