Translating in vitro CFTR rescue into small molecule correctors for cystic fibrosis using the Library of Integrated Network-based Cellular Signatures drug discovery platform

by Selleckchem | Dec 29 2023

Cystic fibrosis (CF) is a lethal autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The common ΔF508-CFTR mutation results in protein misfolding and proteasomal degradation. If ΔF508-CFTR trafficks to the cell surface, its anion channel function may be partially restored. Several in vitro strategies can partially correct ΔF508-CFTR trafficking and function, including low-temperature, small molecules, overexpression of miR-138, or knockdown of SIN3A. The challenge remains to translate such interventions into therapies and to understand their mechanisms. One approach for connecting such interventions to small molecule therapies that has previously succeeded for CF and other diseases is via mRNA expression profiling and iterative searches of small molecules with similar expression signatures. Here, we query the Library of Integrated Network-based Cellular Signatures using transcriptomic signatures from previously generated CF expression data, including RNAi- and low temperature-based rescue signatures. This LINCS in silico screen prioritized 135 small molecules that mimicked our rescue interventions based on their genomewide transcriptional perturbations. Functional screens of these small molecules identified eight compounds that partially restored ΔF508-CFTR function, as assessed by cAMP-activated chloride conductance. Of these, XL147 rescued ΔF508-CFTR function in primary CF airway epithelia, while also showing cooperativity when administered with C18. Improved CF corrector therapies are needed and this integrative drug prioritization approach offers a novel method to both identify small molecules that may rescue ΔF508-CFTR function and identify gene networks underlying such rescue.

Comments:

It sounds like you're discussing research strategies and potential interventions for addressing the challenges posed by the ΔF508 mutation in the CFTR gene, which is associated with cystic fibrosis (CF). The quest to correct the trafficking and function of ΔF508-CFTR has seen various approaches, including in vitro methods like low-temperature treatment, small molecule interventions, miR-138 overexpression, and SIN3A knockdown.

This specific approach you've mentioned involves using the Library of Integrated Network-based Cellular Signatures (LINCS) to analyze transcriptomic signatures from CF expression data. By screening small molecules that mimic the gene expression patterns of successful interventions, researchers identified 135 compounds that showed promise in mimicking the rescue interventions. Subsequent functional screening narrowed this down to eight compounds that partially restored ΔF508-CFTR function, particularly one called XL147 that exhibited promising results in primary CF airway epithelia. Moreover, the combination of XL147 with C18 showed cooperativity in rescuing ΔF508-CFTR function.

This integrative drug prioritization approach not only identifies potential small molecules that might restore ΔF508-CFTR function but also sheds light on the gene networks involved in such rescue mechanisms.

It's exciting to see these innovative approaches aimed at improving therapies for CF, especially in targeting specific mutations like ΔF508-CFTR. The success of XL147, particularly in primary CF airway cells, is encouraging and underscores the potential for further development of CF corrector therapies.