Ex vivo model predicted in vivo efficacy of CFTR modulator therapy in a child with rare genotype

Abstract

Background New drugs that target the basic defect in cystic fibrosis (CF) patients may now be used in a large number of patients carrying responsive mutations. Nevertheless, further research is needed to extend the benefit of these treatments to patients with rare mutations that are still uncharacterized in vitro and that are not included in clinical trials. For this purpose, ex vivo models are necessary to preliminary assessing the effect of CFTR modulators in these cases. Method We report the clinical effectiveness of lumacaftor/ivacaftor therapy prescribed to a CF child with a rare genetic profile (p.Phe508del/p.Gly970Asp) after testing the drug on nasal epithelial cells. We observed a significant drop of the sweat chloride value, as of the lung clearance index. A longer follow‐up period is needed to define the effects of therapy on pancreatic status, although an increase of the fecal elastase values was found. Conclusion Drug response obtained on nasal epithelial cells correlates with changes in vivo therapeutic endpoints and can be a predictor of clinical efficacy of novel drugs especially in pediatric patients.

Elexacaftor–Tezacaftor–Ivacaftor Therapy for Cystic Fibrosis Patients with The F508del/Unknown Genotype

“…Finally, with this work we stress the importance of this kind of ex vivo models for the functional characterization of CFTR rare mutations to predict the drugs responsiveness regardless of the CFTR genotype [18]. Based on our data, we add further evidence in the literature, confirming the validity of functional studies on nasal cells in the cystic fibrosis theratyping and personalized medicine.…”

“…In the setting of such studies, the concept of "minimal function" could be interpreted in an innovative way. We have studied several other patients with this approach [15,16] and recently it was possible to begin a treatment with ivacaftor in a subject with a rare mutation, on the basis of the demonstration of functional studies on nasal epithelial cells [17,18]. Here we show the use of epithelial nasal cells from patients as ex vivo model to evaluate the Kaftrio TM responsiveness on three CF patients with F508del/unknown genotype.…”

Effectiveness of Elexacaftor/Tezacaftor/Ivacaftor Therapy in Three Subjects with the Cystic Fibrosis Genotype Phe508del/Unknown and Advanced Lung Disease

“…International projects to evaluate the efficacy of new molecules on organoids from intestinal or nasal cells from patients with CF with rare mutations are ongoing, but such models are invasive and expensive [28][29][30]. The model of human nasal epithelial cells is a rapid, minimally invasive and effective tool to investigate the effect of novel variants and to assess the effect of novel molecular therapies in individual patients [30][31][32][33][34]. Indeed, we recently reported on treatment with ivacaftor of a child with a rare CFTR variant, on the basis of the demonstration of the positive effect on the CFTR gating activity recorded on nasal epithelial cells [34].…”

“…Indeed, we recently reported on treatment with ivacaftor of a child with a rare CFTR variant, on the basis of the demonstration of the positive effect on the CFTR gating activity recorded on nasal epithelial cells [34]. Therefore, drug response obtained in ex vivo testing correlates with changes in in vivo therapeutic endpoints [33].…”

Elexacaftor–Tezacaftor–Ivacaftor Therapy for Cystic Fibrosis Patients with the F508del/Unknown Genotype

“…In the setting of such studies, the concept of "minimal function" could be interpreted in an innovative way. We have studied several other patients with this approach [12,13] and recently it was possible to begin a treatment with ivacaftor in a subject with a rare mutation, on the basis of the demonstration of functional studies on nasal epithelial cells [14,15]. Here we show the use of epithelial nasal cells from patients as ex-vivo model to evaluate the Trikafta responsiveness on three CF patients with F508del/unknown genotype.…”