EPS3.10 Novel CFTR modulator combinations directly address the ΔF508-CFTR NBD1 stability defect and enable full CFTR correction

Abstract

Objectives: CFTR mutations cause Cystic Fibrosis (CF). CFTR modulating drugs have improved CF outcomes, however, current drugs do not restore normal CFTR function to most patients. ΔF508, the most prevalent CF mutation, causes a loss of F508 within CFTR’s first Nucleotide Binding Domain (NBD1). This destabilizes NBD1 and impairs CFTR folding and function. ΔF508 also impairs CFTR domain-domain assembly, weakening the interface of NBD1 with CFTR’s fourth intracellular loop (ICL4) and transmembrane domain 1 (TMD1). Combining CFTR suppressor mutations that stabilize NBD1 with others that improve CFTR assembly can correct ΔF508 to wild-type (WT) levels. Without NBD1 stabilization, correction is significantly reduced. Drugs that stabilize NBD1 thus have the potential to improve treatment, but no current drugs fully address this defect. To restore WT function to ΔF508-CFTR, Sionna aims to discover and develop small molecule NBD1 stabilizers and CFTR assembly correctors for use in combination.