Precision therapy of CF by modulators is used for common CFTR mutations. However, its effectiveness on the large number of rare mutations is unknown. The main focus of this project is called “theratyping”, which is the testing of the effectiveness of drugs already in clinical use for CF also on rare CFTR mutations at the cellular level.
Respiratory cells and organoids were obtained from the nasal epithelium of CF individuals with different CFTR mutations using an innovative approach.
During this project, 69 patient-derived cell cultures, with 50 different genotypes (44 of which are rare since they don’t carry the F508del mutation and mostly unexplored for therapeutic response to modulators) have been obtained and studied. Overall (including also previous FFC projects), researchers have obtained 111 cultures, with 82 different genotypes (69 of which are rare). Organoids (which can be considered as a small reproduction of organs, in this case lungs, in the laboratory) were also obtained.
The tests applied concerned the genetic characterization and the analysis of CFTR quantity and function. The different therapeutic treatments used were ETI (elexacaftor/tezacaftor/ivacaftor), a new combination of modulators (elexacaftor/lumacaftor/ivacaftor) and a new experimental drug, possibly useful for a new therapy (called “amplificatory therapy”).
Patient-specific cells were studied for CFTR functionality and response to therapeutic treatments, and the effectiveness of treatments was evaluated by several tests: as expected, all genotypes with F508del responded to Kaftrio and to the new combination of modulators, compared with the 74% of rare genotypes without the F508del mutation.
A great variability between individuals with CF has been found in the CFTR quantity and function, mostly unrelated to the CFTR mutations and which can affect the therapeutic response. The possible amplificatory therapy was able to enhance the CFTR quantity and function.
These results highlight a possible effective treatment of individuals with CF whose cells proved to be responsive. This could help to overcome the not eligibility to Kaftrio of the corresponding CF individuals with rare mutations. The new amplificatory drug seems to be promising as a future new precision therapy for CF, possibly in combination with modulatory therapy.