Sodium Transport Inhibitors for Hypertension and Cystic Fibrosis Scientific Summary Description Hypertension is a confounding multifactorial disorder that affects millions of patients worldwide. Cystic fibrosis (CF) is an inherited disease of the pulmonary and gastrointestinal systems that presents in pediatric and young adult populations. What do hypertension and cystic fibrosis (CF) have in common? The central common feature is enhanced absorptive sodium (Na+) transport. Heightened Na+ transport across renal epithelial cells in the latter segments of the nephron of the kidney drives hypertension; accelerated salt absorption across respiratory epithelial cells causes airway surface dehydration in CF. A cardinal rule in vascular physiology is that 2 x plasma Na+ concentration equates with normal plasma osmolality and sets plasma volume and blood pressure, the physiological parameter that is elevated in hypertension. The balance of chloride secretion and Na+ absorption sets the depth of hydration of the ciliated layer on the airway epithelial cell surface. A recent mouse model of CF where an epithelial Na+ channel (ENaC) is conditionally upregulated has proven to be the best mouse model mimicking CF lung disease. Knockouts of the CF gene itself have not been as successful. DiscoveryBioMed, Inc. (DBM) has developed a novel and electrical high-throughput molecular screening format where Na+ transport inhibitors (NTIs) will be discovered via assessment of Na+ transport across polarized epithelial cell models of the renal collecting duct and the CF airway. Na+ transport proteins are the shared molecular target for both disease platforms. ENaC and other epithelial Na+-permeable channels and transporters are notoriously difficult to study outside of a polarized epithelial cell format. Because of this fact, DBM has developed this novel electrical HTS method to screen panels of molecular libraries on polarized epithelial cell models from the kidney (to find potential therapeutics to fight hypertension) and the airways (to find potential therapeutics to fight CF). DBM holds a core principle that drug discovery is accelerated if the screening is performed on an epithelial cell model of disease that maintains in vivo characteristics. DBM has found hit compounds through its novel electrical HTS bioassay that are inhibitors of Na+ transport in kidney collecting duct epithelia, CF airway epithelia or both. The central hypothesis of this Phase 1 SBIR proposal is that novel NTIs will be found that will be developed into viable therapeutics for both hypertension as a large market disease and CF as a niche market disease. This Phase 1 SBIR program has 2 milestones. Milestone 1 aims to select, perfect and optimize the use of polarized kidney collecting duct and airway epithelial cell models for electrical HTS for Na+ transport inhibitors. Milestone 2 is to complete a pilot screen of 15,000 compounds and to validate, compare and contrast the hit compounds found from the pilot electrical screen with additional Na+ transport-relevant assays. The over-arching goal of this work is to identify small molecules that may attenuate enhanced Na+ transport that fuels hypertension, CF or both human diseases, compounds that may eventually be transformed into new therapeutics for these diseases. ? ?
? Hypertension is a debilitating and common disorder that often takes root in the kidney and the vascular system. Upregulation of the activity of proteins in cells that regulate plasma salt and blood pressure, often in the kidney, are routinely involved in renal hypertensive disorders, chronic kidney diseases with hypertension, and vascular diseases. Cystic fibrosis is a disease of children and young adults that causes mortality due to its progressive and debilitating lung disease. Accelerated absorption of salt dehydrates the airways and cause sticky mucus accumulation that eventually obstructs airflow leading to pulmonary decline. Our company seeks to find inhibitors of elevated salt transport that confound and accelerate the progression of multiple human diseases. ? ? ?
