Cystic fibrosis (CF) is caused by mutations in the CFTR gene. Over 2,000 variants have been identified, including stop and splicing mutations that result in reduced or absent CFTR production. CFTR modulator drugs are largely ineffective in cases where the protein is not produced. This project aims to develop a strategy based on antisense oligonucleotides (ASOs), used alone or in combination with modulators, to restore mutant RNA expression and increase the amount of functional CFTR protein. 

ASOs are short synthetic single-stranded molecules designed to bind specifically to target RNA. ASOs can regulate gene expression by promoting mRNA degradation, modulating splicing, activating or inhibiting translation.

ASOs have already demonstrated effectiveness in other genetic diseases. Preliminary data show that in cells with specific mutations, ASOs increase both the quantity and activity of CFTR protein and improve respiratory epithelial function, with additional benefits when combined with existing modulators. Here, this strategy will be further developed and tested, including the evaluation of ASO specificity 

to ensure that treatment does not interfere with the activity of the native CFTR protein.

The most effective ASO candidates will be tested on primary bronchial and nasal epithelial cells derived from people with CF with stop or splicing mutations (obtained through FFC Research’s Primary Culture Service), both in homozygous and heterozygous forms.

The ultimate goal is to contribute to the development of new therapeutic options for people with CF who are unresponsive to currently available CFTR modulators.