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Principal Investigator: Robert Tarran
Organization: UNIVERSITY OF KANSAS MEDICAL CENTER
Fiscal Year: 2024
Award: $542,500
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
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. Orai1 is a
ubiquitously expressed plasma membrane Ca2+ channel that is upstream and regulates neutrophilic
inflammation. Our preliminary data indicate (i) that Orai1 levels remain elevated in CF patient neutrophils
regardless of Trikafta treatment and (ii) that Orai1 levels inversely correlate with CF patient FEV1. Thus, there
is a critical unmet need for novel, CFTR mutation-agnostic therapies to reduce neutrophilic inflammation and
prevent further CF lung damage. Given Orai1’s proximal role in the immune response, Orai1 is thus an attractive
target whose inhibition is predicted to help resolve CF inflammation. We have developed a robust, novel
peptidomimetic called ELD607, which potently inhibits Orai1, and is stable in proteolytically-rich CF sputum. In
murine lung infection models with common CF pathogens including P. aeruginosa and S. aureus, a single,
inhaled dose of ELD607 reduced lung inflammation by 90% and increased survival by ~50%. 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 may be beneficial for the treatment of CF.
However, ELD607 is limited by solubility. In this Catalyst application, for Phase 1, we will optimize ELD607
structure and/or formulation to increase its solubility. For Phase 2, we will determine the maximum tolerated dose
and pharmacokinetics of the fully optimized ELD607, determine ELD607’s specificity for Orai1 vs other Ca2+
channels and test the hypothesis that ELD607 is an allosteric Orai1 modulator that causes Orai1 degradation,
rather than acting as a traditional channel pore blocker. We anticipate that these data will help differentiate
ELD607 from existing pore-blocking Ca2+ channel antagonists and help make it ready for advancement into
clinical trials.
Terms: <ARDS><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Bacteria><Bacterial Infections><Basal Transcription Factor><Basal transcription factor genes><Binding><Biologic Models><Biological Models><Birth><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><C-terminal><CF airway><CF lung disease><CF patients><CF sputum><CFTR><CFTR Protein><COPD><COVID infected patient><COVID patient><COVID positive patient><COVID-19 infected patient><COVID-19 patient><COVID-19 positive patient><COVID19 patient><COVID19 positive patient><Cell Communication and Signaling><Cell Signaling><Cell membrane><Chronic><Chronic Obstruction Pulmonary Disease><Chronic Obstructive Lung Disease><Chronic Obstructive Pulmonary Disease><Clinical Trials><Common Rat Strains><Cystic Fibrosis><Cystic Fibrosis Transmembrane Conductance Regulator><Cystic Fibrosis sputum><Cytoplasmic Membrane><Da Nang Lung><Data><Dehydration><Dose><Drug Kinetics><Equilibrium><Esteroproteases><FEV1><FEV1%VC><Forced Expiratory Volume 1 Test><Forced Expiratory Volume in 1 Second><Formulation><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Alteration><Genetic Change><Genetic Diseases><Genetic defect><Grant><Granulocyte Elastase><Hydrogen Oxide><Immune><Immune response><Immunes><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunological response><Immunosuppressed Host><Inflammation><Inflammatory><Inflammatory Response><Inhalation><Inhaling><Intermediary Metabolism><Intracellular Communication and Signaling><Lead><Leukocyte Elastase><Lung><Lung Diseases><Lung Inflammation><Lung Respiratory System><Lung damage><Lung infections><Lysosomal Elastase><Lysosomes><Marrow Neutrophil><Maximal Tolerated Dose><Maximally Tolerated Dose><Maximum Tolerated Dose><Mediating><Metabolic Processes><Metabolism><Mice><Mice Mammals><Model System><Modeling><Modification><Molecular Interaction><Mucous body substance><Mucoviscidosis><Mucus><Murine><Mus><Mutation><Nasal Epithelium><Neutrophil Elastase><Neutrophilia><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Nonsense Mutation><Normal Range><Normal Values><P aeruginosa><P. aeruginosa><PFT/FEV1><PMN Elastase><Palate><Parturition><Patients><Pb element><Peptidases><Peptide Hydrolases><Peptides><Pharmacokinetics><Phase><Physiologic><Physiological><Plasma Membrane><Pneumonitis><Polymorphonuclear Cell><Polymorphonuclear Leukocyte Elastase><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Population><Protease Gene><Proteases><Proteinases><Proteins><Proteolytic Enzymes><Pseudomonas aeruginosa><Pseudomonas pyocyanea><Public Health><Pulmonary Cystic Fibrosis><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Function Test/Forced Expiratory Volume 1><Pulmonary Inflammation><Rat><Rats Mammals><Rattus><Regulator Genes><Role><S aureus><S. aureus><SARS-CoV-2 infected patient><SARS-CoV-2 patient><SARS-CoV-2 positive patient><Safety><Shock Lung><Signal Transduction><Signal Transduction Systems><Signaling><Sodium Chloride><Solubility><Specificity><Sputum><Staph aureus><Staphylococcus aureus><Stiff lung><Structure><Testing><Transcription Factor Proto-Oncogene><Transcription factor genes><Transcriptional Regulatory Elements><Water><antagonism><antagonist><bacteria infection><bacterial disease><balance><balance function><biological signal transduction><body water dehydration><catalyst><chronic infection><chronic obstructive pulmonary disorder><common symptom><coronavirus disease 2019 infected patient><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19 patient><coronavirus patient><cystic fibrosis airway><cystic fibrosis lung><cystic fibrosis lung disease><cystic fibrosis patients><cystic fibrosis transmembrane regulator><cytokine><design><designing><disease of the lung><disorder of the lung><druggable target><experiment><experimental research><experimental study><experiments><genetic condition><genetic disorder><genome mutation><heavy metal Pb><heavy metal lead><host response><immune system response><immunoresponse><immunosuppressed patient><individuals with CF><individuals with cystic fibrosis><inhibitor><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><lung disorder><lung function><lung injury><mouse model><mucous><murine model><neutrophil><non-sense mutation><novel><pathogen><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><patients with CF><patients with cystic fibrosis><peptide mimetic><peptide mimic><peptide structure><peptidomimetics><peripheral blood><persistent infection><plasmalemma><preservation><prevent><preventing><pulmonary><pulmonary damage><pulmonary function><pulmonary infections><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><regulatory gene><salt><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><small molecule><social role><trans acting element><transcription factor><wet lung>