Selective amino acid formulation enhances anion secretion and restores function in cystic fibrosis mutations.

Introduction: In cystic fibrosis (CF), most CFTR mutations cause partial (Class II) or complete (Class I) loss of function. Modulators (VX) can improve CFTR function in Class II mutations but are ineffective for Class I mutations and may cause side effects, resulting in tolerability issues with concerns about long-term safety. Apical anion secretion, essential for maintaining airway surface liquid (ASL) homeostasis, is regulated by CFTR. Alternative anion channels, like ANO1 and SLC26A9, also contribute to ASL homeostasis. Our recent work indicates that specific amino acids can modulate ion channel expression, activity, and trafficking in epithelial cells. We developed a select amino acid formulation (SAA) to enhance anion secretion in primary human bronchial epithelial cells (HBEC) with CF, regardless of mutation. Methods: Transepithelial short-circuit current was measured in wildtype (WT)- and CF-HBEC with various Class I and Class II mutations. Cells were pretreated with DMSO or VX for 24 h before apical exposure to SAA in Ussing chambers. Benzamil-insensitive current was sequentially inhibited to determine the contributions of SLC26A9, CFTR, ANO1, and NKCC1. Results: SAA increased benzamil-insensitive current to 70%-85% of WT cells, and enhanced Discussion: SAA enhances chloride secretion through SLC26A9 and partial CFTR rescue in Class I and II mutations. These findings suggest SAA functions as a mutation-agnostic therapy to improve anion secretion and clinical symptoms, particularly in Class I mutations.