TY - JOUR
T1 - Amphotericin B induces epithelial voltage responses in people with cystic fibrosis
AU - Chorghade, Rajeev S.
AU - Kim, Bo Ram
AU - Launspach, Janice L.
AU - Karp, Philip H.
AU - Welsh, Michael J.
AU - Burke, Martin D.
N1 - Funding Information:
This work was supported by the National Institutes of Health ( 5R35GM118185 to M.D.B. and HL091842 to M.J.W.), and by Emily's Entourage. M.J.W. is an HHMI Investigator.
PY - 2021/5
Y1 - 2021/5
N2 - 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.
AB - 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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U2 - 10.1016/j.jcf.2020.11.018
DO - 10.1016/j.jcf.2020.11.018
M3 - Article
C2 - 33309058
VL - 20
SP - 540
EP - 550
JO - Journal of Cystic Fibrosis
JF - Journal of Cystic Fibrosis
SN - 1569-1993
IS - 3
ER -