Pharmacological strategies to target nonsense mutations in cystic fibrosis
Awardee: Luis Juan Vicente Galietta
Institution: Fondazione Telethon - TIGEM
Award Amount: $54,718
Final Report Lay Summary:
Cystic fibrosis (CF), one of most frequent and severe genetic diseases, affects multiple organs but
the consequences to the lungs are the most important ones for morbidity and mortality. The basic
defect in CF is the loss of function of CFTR, a plasma membrane chloride channel expressed in
various epithelial cell types. There are multiple types of CF-causing mutations that impair the
expression, maturation, and/or gating of CFTR protein. Importantly, some types of CFTR mutants
can be treated with drugs named correctors and potentiators. However, nonsense mutations, also
known as premature termination codons (PTCs), which cause the production of a truncated CFTR,
remain without an effective treatment. The overall goal of our project was to develop strategies to
target PTCs. In our experiments, cells expressing mutant CFTR were treated with combinations of
compounds acting at different levels on CFTR biosynthesis and function. We have identified the
most effective treatments for each mutation. In particular, we found that W1282X is the most
sensitive mutation with a large recovery mutant CFTR function, close to 30% of normal CFTR.
Y122X, G542X, and R1162X mutations could be also treated (10% of normal function) using
12 different combinations of compounds. In contrast, R553X mutation was particularly refractory to
pharmacological treatment. The results in our study will pave the way for future clinical trials in
which patients with specific mutations will be treated with the most appropriate compound
combinations.