Cystic Fibrosis

Dear Colleagues,

Cystic fibrosis (CF) is caused by loss-of-function mutations in the CFTR gene, which encodes for the CFTR chloride/bicarbonate channel. These mutations may have pleiotropic effects on the CFTR protein, including processing disruption of, and stability at, the plasma membrane (PM) and chloride channel activity. Over the last decade, novel drugs, called modulators, have been developed to rescue the basic defect caused by specific mutations. Because of this complex disease etiology, a combination of CFTR modulators is generally required to rescue the trafficking and functional defects of disease-associated CFTR variants. Due to these disease-modifying treatments, unprecedented clinical results have been achieved in people with eligible CF genotypes. However, real-world data show that there are still a considerable number of people with CF, with covered mutations, who may benefit from alternative modulator therapies. These unconventional candidates may address heterogeneity in patient response, as well as promoting increased market competition and providing increased global access. Moreover, we must consider that CF is characterized by remarkable allelic heterogeneity. Many patients cannot yet benefit from these treatments, as in the cases of patients carrying rare mutations still missing an approved treatment and unable to be included in clinical trials due to the rarity of their mutations. Indeed, traditional randomized trials would require sample sizes that exceed the entire eligible population. Theratyping procedures by means of in vitro predictive models can facilitate personalized medicine approaches to move therapy forward for all people with CF. Despite these efforts, some CF variants will remain difficult to rescue by “classical” CFTR modulators, and there is the need to develop gene-based therapies able to replace or edit the CFTR gene. Alternative approaches focused on the restoration of epithelial homeostasis by targeting proteins other than CFTR could also constitute mutation-agnostic therapies useful for all the patients regardless their genotypes. This topic on "Cystic Fibrosis" aims to gather reviews and original articles focused on novel, promising therapeutic approaches for this devastating disease at basic, translational and clinical levels, to provide expert insights and perspectives on advances in the field.

Dr. Nicoletta Pedemonte
Dr. Miqueias Lopes Pacheco
Dr. Vito Terlizzi
Dr. Paolo Scudieri
Dr. Fabio Bertozzi
Topic Editors