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Novel Strategies to Clear Bacteria from the CF Lung

清除 CF 肺细菌的新策略

基本信息

批准号：
10544476
负责人：
Saira Ahmad
金额：
$ 99.99万
依托单位：
ELDEC PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-10 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10544476
关键词：
Aerosols Affect Alveolar Macrophages Antimicrobial Effect Bacteria Bacterial Antibiotic Resistance Bacterial Infections Biological Models Birth Burkholderia cepacia Burkholderia cepacia complex Capital Cell membrane Cells Chronic Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Cystic Fibrosis sputum Data Disease Progression Dose Drug Kinetics Effector Cell Equilibrium Ferrets Foundations Genes Genetic Diseases Glosso-Sterandryl Haemophilus influenzae Immune Immune response Immunocompromised Host Immunology Immunomodulators Inflammation Inflammatory Response Inhalation Iowa Leukocyte Elastase Lung Lung diseases Lung infections Mediating Modeling Mucous body substance Mus Mutation Nasal Epithelium Nebulizer Neutrophilia Nonsense Mutation Normal Range Palate Patients Peptide Hydrolases Peptides Peripheral Play Population Privatization Proteins Pseudomonas Pseudomonas aeruginosa Public Health Pulmonary Cystic Fibrosis Pulmonary Function Test/Forced Expiratory Volume 1 Pulmonary Inflammation Reagent Regimen Regulator Genes Role Sodium Chloride Staphylococcus aureus System Testing Therapeutic Translating Universities Water aerosolized antimicrobial base cell type chronic infection clinical development combat cystic fibrosis airway cystic fibrosis infection cystic fibrosis mouse cystic fibrosis patients cytokine disease-causing mutation experimental study improved lung health lung injury methicillin resistant Staphylococcus aureus multidrug-resistant Pseudomonas aeruginosa neutrophil novel novel strategies pathogen peptidomimetics prevent programs pulmonary function

项目摘要

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 such as TRIKAFTA significantly increase CF patient lung function by >10% but do not bring it into the normal range and for patients with pre-existing bacterial lung infections, do not clear bacteria from their lungs. Moreover, these compounds do not treat CF patients with nonsense mutations where no CFTR protein is produced. 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. Orai1 is a ubiquitously expressed plasma membrane Ca2+ channel that regulates inflammation. We found that SPLUNC1 inhibits Orai1. 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 CF mice to understand which immune effector cells are regulated by ELD607. The CF ferret model developed by Dr Engelhardt and coworkers at the University of Iowa spontaneously develops chronic CF lung disease including inflammation and bacterial infection. We will first validate that we can deliver sufficient doses of ELD607 via nebulizer to safely inhibit Orai1 in wild-type and CF ferret lungs. Then we will chronically administer ELD607 to CF ferrets with existing lung disease in order to study the impact of ELD607 on CF disease progression.

囊性纤维化（CF）是一种由囊性纤维化跨膜调节因子突变引起的遗传性疾病