SPYRYX LLC — Department of Health and Human Services SBIR Phase I: NHLBI

Description

The epithelial Na channel ENaC regulates Na absorption across many epithelia In the airways of cystic fibrosis CF patients ENaC is abnormally hyperactive leading to disproportionate Na absorption and a depletion of airway surface liquid ASL volume This contributes to mucus stasis and increased incidence of airway infections that frequently lead to the death of the patient Surprisingly there are no existing therapies to treat abnormal ENaC activity in the lung However biological control of ENaC is complex and offers several opportunities for therapeutic intervention Using a proteomic screen we have identified the protein SPLUNC as a potent allosteric inhibitor of ENaC that binds extracellularly to ENaC reducing the amount of ENaC in the plasma membrane and subsequently limiting ENaC activity After identifying the ENaC inhibitory domain of SPLUNC we have completed screening and lead selection of a peptide for clinical development This peptide robustly inhibits ENaC and prevents ASL hyperabsorption in CF airway cultures for h following a single dose This peptide has completed animal toxicology and is being prepared for First Time in Human dosing CF patients currently face significant treatment burdens with an average time spent on treatment activities of minutes per day If human efficacy studies prove the benefit of the therapy predicted by cell culture and animal models then the peptide will be a disease modifying therapy impacting mucus clearance lung infection and lung capacity when administered as a chronic therapy To deliver these benefits to patients without adding to their treatment burden we seek to develop a dry powder inhaler DPI product presentation We will demonstrate proof of concept for developing a DPI by i evaluating the feasibility of spray drying our peptide to produce a respirable powder and ii demonstrating the biological activity is not altered by spray drying Completion of the proposed work will lead to a Phase II application that will be aimed at scaling the spray drying process and producing material for animal toxicology studies The epithelial sodium channel ENaC is a molecular target for cystic fibrosis CF Aberrant ENaC activity is associated with the accumulation of viscous dehydrated mucus leading to blockage of small airways and bacterial infection is one of the more debilitating manifestations of CF Current treatments are costly and are hampered by the lack of targeted and effective therapeutic targets We have identified a novel peptide agent that inhibits ENaC activity and may provide a valuable new approach for treatment