Emerging preclinical modulators developed for F508del-CFTR have the potential to be effective for ORKAMBI resistant processing mutants

Personalized Medicine Based on Nasal Epithelial Cells: Comparative Studies with Rectal Biopsies and Intestinal Organoids

“…This finding highlights that both cellular models can be used to predict the clinical benefit of a single drug or combination of drugs for a certain individual, despite the fact that CFTR function in pHNEs was measured by an Ussing chamber, whereas in intestinal organoids, it was indirectly measured by organoid swelling. Several groups already use either of these two models to predict responses to CFTR modulator drugs [ 16 , 17 , 18 , 20 , 39 , 40 , 46 , 47 , 48 , 49 ], but here, we show that the establishment of a responder or non-responder was the same in both models ( Figure 3 ), using both types of samples from the same individual. The only exception was the individual with the D614G/F508del genotype who was considered a non-responder through pHNE analysis but appeared as a responder from intestinal organoid data.…”

Potential of Intestinal Current Measurement for Personalized Treatment of Patients with Cystic Fibrosis

“…In addition, nasal or bronchial epithelial cells collected by brushings can be expanded and differentiated under air-liquid interface conditions to enable testing of multiple drug candidates in primary airway epithelial cultures derived from individual patients harboring specific CFTR mutations [ 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ]. Several preclinical studies in these patient-derived model systems showed that the triple combination of elexacaftor–tezacaftor–ivacaftor, as well as several novel modulator combinations improve CFTR function in class II mutations other than F508del , as well as other rare CFTR mutations [ 68 , 69 , 70 , 71 , 72 , 73 , 74 ]. Functional in vitro assays in these patient-derived intestinal and airway model systems were shown to correlate with biomarkers of CFTR function in patients with a spectrum of CFTR mutations associated with a broad range of CFTR modulator responses [ 62 , 75 ].…”

Nasal Epithelial Cell-Based Models for Individualized Study in Cystic Fibrosis

“…Elexacaftor, tezacaftor, and ivacaftor (ETI) therapy has specifically produced robust clinical responses in a large proportion of the CF population, including F508del homozygotes, heterozygotes, and select rare variants identified through heterologous screening assays [ 14 , 15 , 64 ]. Numerous additional corrector and potentiator compounds have been identified, and are in development as possible therapeutics [ 96 , 97 , 98 ]. In addition, other classes of modulator compounds are under study, including those that increase mRNA signal (“amplifiers”), though none of these therapies are currently FDA approved [ 99 , 100 ].…”

“…The processes by which the current correctors improve protein folding and trafficking to the cell surface are not clearly delineated and are likely much more dependent on the intracellular and tissue level milieu, therefore increasing the importance of high fidelity model systems that accurately recapitulate in vivo conditions [ 102 ]. The use of HNE models to meet this need has been instrumental in evaluating the therapeutic potential of small-molecule modulators, as well as in helping to understand the mechanism of action of these molecules and enable the identification of susceptible mutations [ 65 , 95 , 96 , 97 , 103 ]. Nasal cell testing, along with other model systems, has demonstrated the action of elexacaftor as a type 3 corrector compound with efficacy in numerous CFTR variants beyond F508del such as G85E and M1101K CFTR [ 96 ].…”

“…Nasal cell testing, along with other model systems, has demonstrated the action of elexacaftor as a type 3 corrector compound with efficacy in numerous CFTR variants beyond F508del such as G85E and M1101K CFTR [ 96 ]. Indeed, as more modulator therapies are identified, nasal cell models are increasingly useful to quantify response in common and rare CFTR variants, which may aid drug development and approval [ 97 , 103 ]. Patient-derived nasal epithelial models have allowed for flexibility in testing therapeutic response, showing specific promise as a validation tool following profile screening by higher-throughput methodology, gene edited cells, or immortalized cell lines [ 104 ].…”