# Amphotericin B Restoration of Anion Secretion in Cystic Fibrosis Airways

> **NIH NIH P01** · UNIVERSITY OF IOWA · 2021 · $475,325

## Abstract

PROJECT 2
PROJECT SUMMARY
Cystic fibrosis (CF) is caused by loss-of-function mutations in the gene encoding the cystic fibrosis
transmembrane conductance regulator (CFTR) apical membrane anion channel. Loss of CFTR-
mediated HCO3- and Cl- secretion by airway epithelia impairs respiratory host defenses, causing bacterial
infection, inflammation, mucus accumulation, and respiratory failure. One strategy for restoring anion
channel function to the apical membrane is to increase the function of mutant CFTR channels. That has
proven successful for people with specific CFTR mutations. However, ~10% of people with CF have
mutations that do not respond to CFTR modulators or they are not able to take modulators. Another
strategy is to provide an alternative channel. Toward this end, we studied amphotericin B (AmB); earlier
work showed that AmB forms anion channels. We discovered that apical AmB increased HCO3- and
Cl- secretion in cultured CF airway epithelia, including those with CFTR-null mutations. AmB
increased ASL pH, height, and antibacterial activity. AmB is clinically approved to treat fungal infections,
and off-label lung aerosolization has an impressive safety record. Thus, AmB could potentially provide a
new mutation-agnostic therapy for CF lung disease. However, many questions remain unanswered and
we lack important in vivo data. Therefore, our overarching goal is to understand the mechanisms of
AmB-induced anion secretion in airway epithelia and to test the hypothesis that AmB can restore
CF host defenses in vivo. To achieve this goal, we will answer questions in three aims. Aim 1. What
molecular and cellular mechanisms elicit AmB-mediated anion secretion? Without cAMP-dependent
regulation and with half the anion selectivity of CFTR, AmB is an imperfect substitute for CFTR. We will
test key hypotheses about how AmB functions in airway epithelia. Aim 2. Which epithelial cells does
AmB target and how does AmB alter them? These studies will reveal AmB function in large and small
airway epithelia and diverse cell-types, test AmB in airway epithelia remodeled by inflammation, and test
for compensatory changes. Aim 3. Does AmB reverse CF host defense defects in vivo? Using CF pigs,
we will test if nebulized AmB increases ASL pH, increases ASL antimicrobial activity and height,
increases mucociliary transport, and enhances S. aureus eradication from the lungs. The results of
these studies will have direct implications for developing a new genotype agnostic approach to treating
CF, and will inform development of other therapies in Projects 1 and 3. Our proposal’s success is
enhanced by an ongoing collaboration between the labs of Welsh (Iowa) and Burke (Illinois), by
utilization of outstanding cores, and by an environment of cooperation between the Program’s projects
and investigators. With this background, our track record, and our commitment, we believe this research
can change the lives of people with CF.

## Key facts

- **NIH application ID:** 10248529
- **Project number:** 5P01HL152960-02
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** MICHAEL J. WELSH
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $475,325
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10248529

## Citation

> US National Institutes of Health, RePORTER application 10248529, Amphotericin B Restoration of Anion Secretion in Cystic Fibrosis Airways (5P01HL152960-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10248529. Licensed CC0.

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