A Genomic Signature Approach to Rescue DF508-Cystic Fibrosis Transmembrane Conductance Regulator Biosynthesis and Function

The most common cystic fibrosis (CF) mutation, DF508, causes protein misfolding, leading to proteosomal degradation. The autohrs recently showed that expression of miR-138 enhances CF transmembrane conductance regulator (CFTR) biogenesis and partially rescues DF508-CFTR function in CF airway epithelia. They hypothesized that a genomic signature approach can be used to identify new bioactive small molecules affecting DF508-CFTR rescue. The Connectivity Map was used to identify 27 small molecules with potential to restore DF508-CFTR function in airway epithelia. The molecules were screened in vitro for efficacy in improving DF508-CFTR trafficking, maturation, and chloride current. They identified four small molecules that partially restore DF508-CFTR function in primary CF airway epithelia. Of these, pyridostigmine showed cooperativity with corrector compound 18 in improving DF508-CFTR function. There are few CF therapies based on new molecular insights. Querying the Connectivity Map with relevant genomic signatures offers a method to identify new candidates for rescuing DF508-CFTR function.