Novel Strategies to Clear Bacteria from the CF Lung

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Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene. CF airways are immunocompromised and become colonized with bacteria soon after birth. Chronic bacterial infection leads to persistent and severe neutrophil-dominated pulmonary inflammation, high lung protease levels, lung damage and a decline in FEV1. CFTR modulator/correctors from Vertex increase CF patient lung function but do not bring it into the normal range, do not treat CF patients with nonsense mutations and for patients with pre-existing bacterial lung infections, do not clear bacteria from their lungs. Thus, there is a critical unmet need for novel, CFTR mutation-agnostic therapies to help clear bacteria from CF lungs and limit neutrophilic lung damage. Short Palate LUng and Nasal epithelial Clone 1 (SPLUNC1) is a secreted protein that is highly expressed in the lung, where it plays a key role in maintaining lung health. SPLUNC1 is a CF gene modifier, and patients with reduced SPLUNC1 levels have lower FEV1 and exacerbate more frequently. SPUNC1 inhibits Orai1, a ubiquitously expressed plasma membrane Ca2+ channel that regulates inflammation. However, SPLUNC1 is rapidly degraded by neutrophil elastase (NE), which we posit results in greater Orai1 activity and more inflammation. Consistent with this, our preliminary data indicate that Orai1 is upregulated in CF patient lung immune cells. Given Orai1’s proximal role in the immune response, Orai1 is thus an attractive target whose inhibition is predicted to help resolve CF inflammation. Eldec Pharma has developed a robust, novel peptidomimetic called ELD607, which reprises SPLUNC1’s ability to inhibit Orai1, yet is significantly more stable in the presence of NE, and significantly more potent/efficacious. ELD607 is stable in proteolytic CF sputum and inhibits Ca2+-influx in freshly-isolated CF patient peripheral neutrophils and in CF sputum-derived immune cells in a mutation-agnostic fashion. In murine lung infection models with common CF pathogens including P. aeruginosa and S. aureus, a single, inhaled dose of ELD607 reduced lung inflammation (neutrophilia, cytokines, NE) by 90%, decreased lung bacterial infection by 3-4 log10 CFUs and increased survival. In a chronic CF model (SCNN1B mice), ELD607 reduced neutrophilia and increased survival. These experiments demonstrate that rebalancing the lung’s inflammatory response by inhibiting Orai1 enhances the lungs’ natural ability to clear pathogens. In this proposal, we will use wild-type and rats to determine the pharmacokinetics of ELD607 after IV administration and determine its stability in blood. Secondly, we propose to evaluate whether acute and/or chronic administration of ELD607 reduce neutrophilia and /or clear bacteria from CF mice lungs. In terms of training and mentoring, this Diversity Supplement will allow Dr. Sassano to advance her knowledge in the drug development field, as well as permit her to acquire business and development experience to advance her career. Given her background, Dr. Sassano is an excellent candidate to improve diversity at Eldec Pharmaceuticals.