CFTR modulators used to treat cystic fibrosis target the underlying defect of the disease by restoring the function of the defective CFTR protein. Some people with cystic fibrosis still cannot benefit from these therapies because they carry nonsense mutations. These CFTR gene variants introduce a premature stop signal, preventing the production of a full-length, functional CFTR protein. In most cases, they also activate a cellular quality-control mechanism known as Nonsense-Mediated mRNA Decay (NMD), which recognizes the mutant CFTR messenger RNA (mRNA) as defective and degrades it, thereby preventing the production of truncated or aberrant proteins.
This process is regulated by a network of cellular factors, including RNA-binding proteins (RBPs). These proteins bind to messenger RNAs and determine their fate within the cell: some promote mRNA stability, whereas others contribute to its degradation. In the case of CFTR, however, we still do not fully understand which RBPs interact with its mRNA or how they regulate its stability.

This project aims, for the first time, to systematically identify the complete set of proteins that interact with CFTR mRNA and determine how these interactions change in the presence of nonsense mutations, with the goal of identifying new potential therapeutic targets. These studies will be carried out in collaboration with the FFC Ricerca Primary Cell Culture Facility.

In the future, modulating some of these proteins could increase the amount of available CFTR mRNA and, consequently, the production of CFTR protein. This approach could also enhance the effectiveness of other therapeutic strategies by increasing the amount of CFTR protein available for correction by CFTR modulators and by prolonging the stability of mRNA used in mRNA-based therapeutic approaches.