Testing organ-specific responses to therapies in tissues differentiated from Cystic Fibrosis patient derived iPSCs

Area of Science:

• Biomedical research
• Genetics
• Cell biology

Background:

• Cystic Fibrosis (CF) is a genetic disorder caused by CFTR gene mutations.
• Current CF models like nasal cells and rectal organoids show variable therapeutic responses.
• Patient-specific responses to CFTR modulators differ across tissues, necessitating comparative strategies.

Purpose of the Study:

• To evaluate CFTR modulator (Trikafta) efficacy in patient-specific induced pluripotent stem cell (iPSC)-derived colonic and airway cultures.
• To compare therapeutic responses in CF tissues versus isogenic, mutation-corrected controls.
• To establish a framework for comparing CFTR modulator efficacy across pulmonary and extra-pulmonary systems.

Main Methods:

• Utilized patient-specific iPSC-derived colonic and airway epithelial cultures.
• Compared CFTR chloride channel response to Trikafta in CF tissues and mutation-corrected isogenic controls.
• Quantified pharmacological rescue of CFTR function in both tissue types.

Main Results:

• Demonstrated measurable CFTR chloride channel response to Trikafta in both iPSC-derived colonic and airway cultures.
• Showcased successful pharmacological rescue of CFTR function in patient-specific models.
• Validated the approach for comparing therapeutic efficacy in different organoid systems.

Conclusions:

• Patient-specific iPSC-derived colonic and airway models can effectively assess CFTR modulator efficacy.
• This study provides a proof-of-concept for comparing personalized CFTR therapies across multiple organs.
• The developed strategy offers a roadmap for future research into tissue-dependent CF therapeutic responses.