In Italy, many CF people carry rare, orphan mutations. The study aimed to investigate the defect caused by these mutations and to evaluate their responsiveness to modulators, with the ultimate goal of identifying the best therapeutic option available. This was achieved through the use of patients’ nasal cells, collected by nasal brushing and cultured using established methods. These “ex vivo” models were used to study the expression of CFTR, evaluate its activity and response to modulators.
Thanks to the collaboration with various CF centers, 150 individuals were recruited, carrying orphan mutations (such as P5L, G85E, R347P, N1303K, I506V, T1036I, V317A, R1066C, M1V, L1077P and others). Electrophysiological and biochemical studies carried out on nasal cells have allowed to characterize the molecular defect caused by the mutations and the responsiveness to already approved CFTR modulators and compounds in the preclinical phase. Studies have shown that some of these mutations are sensitive to modulators: about 50% of the individuals recruited have a mutation that can be saved by the combined use of a potentiator and correctors and could benefit from treatment with these drugs.
Interesting results also came from the molecular analyzes of the CFTR transcript (i.e. the RNA molecule that carries the information for protein synthesis) in people who carry mutations that cause a shift in the reading code. In these cases, degradation of the transcript, highly aberrant, would be expected, while the project’s results have shown that, when the mutation is in the initial portion of the sequence, the transcript is present and could allow the production of a protein which however lacks the first part of the sequence. The studies of the research team now aim at understanding whether this mutated protein maintains some activity and can be rescued by modulators.
Pubblications
- Armirotti Andrea, Distinctive lipid signatures of bronchial epithelial cells associated with cystic fibrosis drugs, including Trikafta, Journal of Clinical Investigation 14,808 32673287 2020
- Armirotti Andrea, Proteomics and Metabolomics for Cystic Fibrosis Research, International Journal of Molecular Sciences 4,55 32751630 2020
- Millo Enrico, Discovery of novel VX-809 hybrid derivatives as F508del-CFTR correctors by molecular modeling, chemical synthesis and biological assays, European Journal of Medicinal Chemistry 5,57 2020
- Pedemonte Nicoletta, In silico drug repositioning on F508del-CFTR: A proof-of-concept study on the AIFA library, European Journal of Medicinal Chemistry 5,57 33472120 2021
- Pedemonte Nicoletta, Partial Rescue of F508del-CFTR Stability and Trafficking Defects by Double Corrector Treatment, Int. J. Mol. Sci. 5,924 34067708 2021
- Pedemonte Nicoletta, Proteostasis Regulators in Cystic Fibrosis: Current Development and Future Perspectives, Journal of medicinal chemistry 10.1021/acs.jmedchem.1c01897 7.446 35377645 2022
- Pedemonte Nicoletta, Synthesis and biological evaluation of thiazole derivatives on basic defects underlying cystic fibrosis, Bioorganic & Medicinal Chemistry Letters 2,57 32784089 2020
- Sondo Elvira The L467F-F508del Complex Allele Hampers Pharmacological Rescue of Mutant CFTR by Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis Patients: The Value of the Ex Vivo Nasal Epithelial Model to Address Non-Responders to CFTR-Modulating Drugs, Int. J. Mol. Sci. vol. 23,6 3175. 15 Mar. 2022