Abstract
QuestionCystic Fibrosis (CF) is due to pathogenic variants in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Recent improvement enabled pharmacologic therapy aiming at restoring mutated CFTR expression and function. CFTR “modulators” have revolutionised the CF therapeutic landscape, particularly the last approved Trikafta. This drug-combination is indicated by FDA and very recently by EMA for genotypes carrying at least one copy of CFTR with F508del pathogenic variant. However, several genotypes, are not eligible for Trikafta treatment, yet.
Materials/patients and methodsWe exploited an innovative cellular approach allowing highly efficientin vitro-expansion of airway epithelial stem cells (AESC) through conditional reprogramming (CRC) from nasal brushing of CF patients. This approach, coupled to development of AESC-derived personalised disease models, as organoids and air liquid interface (ALI) cultures, revealed highly suitable for CFTR pharmacological-testing.
Results and answer to the questionWe fully validated the experimental models and implemented the CFTR functional assays and biochemical CFTR protein characterisation, that allowed to evaluate the efficacy of clinically available modulators in restoring CFTR maturation and function of each patient-derived “avatar” (theratyping). F508del homozygous genotypes, used as controls, confirmed the higher clinical activity of Trikafta in comparison with older modulators. Trikafta showed its efficacy also on three rare genotypes previously not eligible for modulators-treatment, opening the way to clinical translation. Finally, encouraging results for innovative drug combinations were also obtained.
Footnotes
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Conflict of interest: Giovanni Sette has nothing to disclose.
Conflict of interest: Stefania Lo Cicero has nothing to disclose.
Conflict of interest: Giovanna Blaconà has nothing to disclose.
CConflict of interest: Silvia Pierandrei has nothing to disclose.
Conflict of interest: Sabina Maria Bruno has nothing to disclose.
Conflict of interest: Valentina Salvati has nothing to disclose.
Conflict of interest: Germana Castelli has nothing to disclose.
Conflict of interest: Mario Falchi has nothing to disclose.
Conflict of interest: Benedetta Fabrizzi has nothing to disclose.
Conflict of interest: Giuseppe Cimino has nothing to disclose.
Conflict of interest: Ruggero De Maria has nothing to disclose.
Conflict of interest: Mauro Biffoni has nothing to disclose.
利益冲突:阿德里亚娜Eramohas nothing to disclose.
Conflict of interest: Marco Lucarelli has nothing to disclose.
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