Gene-Corrected Basal Cells Restore CFTR In Vitro; Transplants Regenerate Epithelium in a Preclinical Sinus Model

Area of Science:

• Regenerative Medicine
• Gene Therapy
• Pulmonary Medicine

Background:

• Cystic fibrosis (CF) results from CFTR gene mutations, causing lung disease.
• Current CFTR modulators are ineffective for approximately 10% of patients.
• There is a critical need for mutation-agnostic CF treatments.

Purpose of the Study:

• To evaluate lentiviral vector-mediated CFTR gene addition for restoring CFTR function in airway basal cells from CF patients.
• To assess the in vitro and in vivo regenerative capacity of gene-corrected basal cells.

Main Methods:

• Airway basal cells from 13 pediatric CF participants were transduced with lentiviral vectors carrying wild-type CFTR.
• Transduced cells were cultured in air-liquid interface (ALI) to assess differentiation and CFTR function.
• Gene-corrected rabbit airway basal cells were transplanted into rabbit nasal septa to evaluate in vivo regeneration.

Main Results:

• Transduced basal cells formed functional, pseudostratified mucociliary epithelium with restored CFTR activity, surpassing current modulator efficacy in some cases.
• Combined gene therapy and CFTR modulator treatment (ETI) demonstrated additive benefits.
• In vivo transplantation led to successful engraftment and regeneration of ciliated epithelium, improving nasal airflow and mucociliary clearance.

Conclusions:

• Lentiviral vector-mediated CFTR gene addition effectively restores CFTR function and supports airway epithelial regeneration.
• This platform offers a potential cell therapy for all individuals with CF, regardless of genotype.
• The approach may also be applicable to other upper airway epithelial repair applications.