Previous studies showed a variable response in CFTR activity and rescue of the N1303K variant to approved modulators in primary nasal cells, ranging from very poor to a marked response. We aim now to understand whether this variability may be due to the genetic characteristics of the different individuals that could influence the expression and function of CFTR. The N1303K is the second most common variant in Italian cystic fibrosis (CF) patients, showing both defective maturation and activity.

Understanding the bases of such variability will help to optimize treatment for people with CF carrying this variant. In particular, the researchers will investigate the genetic characteristics of the different individuals looking for the presence of additional sequence changes that might influence either the amount or the maturation and function of the mutated N1303K protein. The aim of the project is to provide a quantitative evaluation of the CFTR gene expression in primary cells derived from people with CF and carrying the N1303K mutation and showing different sensitivity to CFTR modulators. The study will also provide indications about the possible correlation between the expression level of the mutant N1303K CFTR and the variable drug response observed. Furthermore, understanding the basis of the variable response of N1303K to available drugs can increase our knowledge of the basic mechanisms regulating CFTR protein expression and therefore will likely foster and inform the development of new pharmacological agents. The identification of groups of people with CF potentially responsive to drugs already available for the treatment is essential to provide the scientific evidence necessary to promote access to drugs for these people.