Rajeev S Chorghade1, Bo Ram Kim2, Janice L Launspach2, Philip H Karp2, Michael J Welsh3, Martin D Burke4. 1. Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. 2. Department of Internal Medicine and HHMI, Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. 3. Department of Internal Medicine and HHMI, Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. 4. Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana IL, USA; Arnold and Mabel Beckman Institute, University of Illinois at Urbana-Champaign, Urbana IL, USA; Carle Illinois College of Medicine, University of Illinois at Urbana-Champaign, Champaign, IL 61820, USA; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana IL, USA. Electronic address: mdburke@illinois.edu.
Abstract
BACKGROUND: Approximately 10% of people with cystic fibrosis (CF) have mutations that result in little to no CFTR production and thus cannot benefit from CFTR modulators. We previously found that Amphotericin B (AmB), a small molecule that forms anion channels, restored HCO3- secretion and increased host defenses in primary cultures of CF airway epithelia. Further, AmB increased ASL pH in CFTR-null pigs, suggesting an alternative CFTR-independent approach to achieve gain-of-function. However, it remains unclear whether this approach can be effective in people. METHODS: To determine whether AmB can impact physiology in people with CF, we first tested whether Fungizone, a clinically approved AmB formulation, could cause electrophysiological effects consistent with anion secretion in primary cultures of CF airway epithelia. We then evaluated the capacity of AmB to change nasal potential difference (NPD), a key clinical biomarker, in people with CF not on CFTR modulators. RESULTS: AmB increased transepithelial Cl- current and hyperpolarized calculated transepithelial voltage in primary cultures of CF airway epithelia from people with two nonsense mutations. In eight people with CF not on CFTR modulators, intranasal Fungizone treatment caused a statistically significant change in NPD. This change was similar in direction and magnitude to the effect of ivacaftor in people with a G551D mutation. CONCLUSIONS: Our results provide the first evidence that AmB can impact a clinical biomarker in people with CF. These results encourage additional clinical studies in people with CF to determine whether small molecule anion channels can provide benefit.
BACKGROUND: Approximately 10% of people with cystic fibrosis (CF) have mutations that result in little to no CFTR production and thus cannot benefit from CFTR modulators. We previously found that Amphotericin B (AmB), a small molecule that forms anion channels, restored HCO3- secretion and increased host defenses in primary cultures of CF airway epithelia. Further, AmB increased ASL pH in CFTR-null pigs, suggesting an alternative CFTR-independent approach to achieve gain-of-function. However, it remains unclear whether this approach can be effective in people. METHODS: To determine whether AmB can impact physiology in people with CF, we first tested whether Fungizone, a clinically approved AmB formulation, could cause electrophysiological effects consistent with anion secretion in primary cultures of CF airway epithelia. We then evaluated the capacity of AmB to change nasal potential difference (NPD), a key clinical biomarker, in people with CF not on CFTR modulators. RESULTS: AmB increased transepithelial Cl- current and hyperpolarized calculated transepithelial voltage in primary cultures of CF airway epithelia from people with two nonsense mutations. In eight people with CF not on CFTR modulators, intranasal Fungizone treatment caused a statistically significant change in NPD. This change was similar in direction and magnitude to the effect of ivacaftor in people with a G551D mutation. CONCLUSIONS: Our results provide the first evidence that AmB can impact a clinical biomarker in people with CF. These results encourage additional clinical studies in people with CF to determine whether small molecule anion channels can provide benefit.
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