CFTR function and clinical response to modulators parallel nasal epithelial organoid swelling

Area of Science:

• Biomarkers
• Cell biology
• Medical research

Background:

• Developing in vitro biomarkers for cystic fibrosis transmembrane conductance regulator (CFTR) activity is crucial for personalized modulator selection and clinical trials.
• Current methods require improvement for assessing individual patient responses to CFTR modulators.

Purpose of the Study:

• To develop and validate an organoid swelling assay using human nasal epithelial cells as a functional biomarker for CFTR activity.
• To assess the assay's correlation with established ion channel measurements and clinical outcomes.

Main Methods:

• Human nasal epithelial cells were obtained via brush biopsies and cultured as organoids or monolayers.
• Organoids underwent a functional swelling assay with automated imaging and analysis.
• Monolayers were used for short-circuit current measurements to assess ion channel activity.
• Assay data were correlated with short-circuit current measurements and clinical data from patients on modulators.

Main Results:

• The organoid swelling assay demonstrated a strong correlation with short-circuit current measurements of ion channel activity.
• The assay successfully distinguished individual patient responses and differences between patient groups.
• It accurately reflected incremental drug responses to various CFTR modulator therapies, including monotherapy and combination treatments.
• Swelling activity in the assay paralleled observed clinical responses in patients.

Conclusions:

• An in vitro organoid swelling assay using patient-derived cells serves as a reliable biomarker for predicting drug responses in cystic fibrosis.
• This assay is valuable for preclinical drug development, aiding in the creation of novel treatments.
• It holds potential as a clinical trial outcome measure for various therapeutic strategies, including gene therapy and gene editing.