Amyloid Precursor Protein (APP) is not Essential for the Observed Reduction in Epithelial Sodium Channel (ENaC) Activity After Treatment with the Cereblon Modulator CC-90009
Year: 2025
Type: dissertation
Abstract: Cereblon E3 Ligase Modulating Drugs (CELMoDs) have the potential to treat rare variants of cystic fibrosis (CF) caused by premature termination codons. One such drug, CC-90009, which results in degradation of several cell proteins, rescued the function of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein in CF human bronchial epithelial cells (HBECs). CC-90009 also decreased epithelial sodium channel (ENaC) activity, which could be additionally therapeutic for individuals with CF. The mechanism by which ENaC activity was reduced by CC-90009 is unknown. Here, we tested the hypothesis that degradation of amyloid precursor protein (APP), a putative CC-90009 target, is involved in ENaC reduction. CRISPR/Cas9 knockdown of APP was performed in HBEC cell lines and the resulting electrophysiological phenotype was studied using a 24-channel transepithelial current clamp amplifier (TECC). In both non-CF and CF cell cultures, knockdown of APP did not impact ENaC activity. Thus, APP is not essential for ENaC reduction after treatment with CC-90009. To inform the development of new therapies for people with CF, further studies are needed to identify mechanisms whereby CC-90009 reduces ENaC activity.
DOI: 10.17615/1yjh-2s37
Author: Venable, Kiana
Institution: University of North Carolina at Chapel Hill
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W6944364806
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