{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:49:59Z","timestamp":1782280199714,"version":"3.54.5"},"posted":{"date-parts":[[2025,6,24]]},"group-title":"Pharmacology and Toxicology","reference-count":33,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T00:00:00Z","timestamp":1750723200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"cystetic Medicines Inc.","award":["C0673 Studies with Amphotericin B Cystetic for Inhalation"],"award-info":[{"award-number":["C0673 Studies with Amphotericin B Cystetic for Inhalation"]}]},{"name":"NIH","award":["NIH R35GM118185 to MDB"],"award-info":[{"award-number":["NIH R35GM118185 to MDB"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,6,24]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Cystic Fibrosis (CF) is caused by loss-of-function mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel predominantly expressed on the apical membrane of epithelial cells. Reduced Cl\n                  <jats:sup>\u2212<\/jats:sup>\n                  and HCO\n                  <jats:sub>3<\/jats:sub>\n                  <jats:sup>\u2212<\/jats:sup>\n                  secretion due to dysfunctional CFTR results in a decrease in lung function and is the leading cause of morbidity in individuals with CF. Recent therapies, known as highly effective CFTR modulator therapy (HEMT), help improve the lung function in individuals with specific CF-causing mutations by enhancing the folding, trafficking, and gating of CFTR. However, variability in HEMT responsiveness leads to sub-optimal clinical outcomes in some people with CF undergoing modulator therapy. A potential strategy is to complement their function with a CFTR-independent mechanism. One possibility is the use of ion channel-forming small molecules such as amphotericin B, which has shown promise in restoring function and host defenses in CF airway disease models. Amphotericin B functions as a molecular prosthetic for CFTR and may thus complement CFTR modulators. Here we show that co-treatment of CF airway epithelia with HEMT and amphotericin B results in greater increases in both HCO\n                  <jats:sub>3<\/jats:sub>\n                  <jats:sup>\u2212<\/jats:sup>\n                  secretory flux and ASL pH compared to treatment with either agent alone. These findings suggest that co- administration of CFTR modulators and molecular prosthetics may provide additive therapeutic benefits for individuals with CF.\n                <\/jats:p>","DOI":"10.1101\/2025.06.18.660463","type":"posted-content","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T19:40:16Z","timestamp":1750794016000},"source":"Crossref","is-referenced-by-count":0,"title":["Molecular prosthetics and CFTR modulators additively increase secretory HCO\n                  <sub>3<\/sub>\n                  <sup>\u2212<\/sup>\n                  flux in cystic fibrosis airway epithelia"],"prefix":"10.64898","author":[{"given":"Nohemy","family":"Celis","sequence":"first","affiliation":[{"name":"Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danforth P.","family":"Miller","sequence":"additional","affiliation":[{"name":"cystetic Medicines, Inc., San Carlos, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas E.","family":"Tarara","sequence":"additional","affiliation":[{"name":"cystetic Medicines, Inc., San Carlos, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffry G.","family":"Weers","sequence":"additional","affiliation":[{"name":"cystetic Medicines, Inc., San Carlos, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian M.","family":"Thornell","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Molecular Physiology and Biophysics, Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Welsh","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Molecular Physiology and Biophysics, Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7963-7140","authenticated-orcid":false,"given":"Martin D.","family":"Burke","sequence":"additional","affiliation":[{"name":"Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA"},{"name":"cystetic Medicines, Inc., San Carlos, CA, 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