Airway epithelial CFTR mRNA expression in cystic fibrosis patients after repetitive administration of a recombinant adenovirus.

Area of Science:

• Gene Therapy
• Respiratory Medicine
• Molecular Biology

Background:

• Cystic fibrosis (CF) is a genetic disorder affecting the lungs.
• Gene therapy aims to deliver functional CFTR cDNA to correct CFTR deficiency.
• Adenovirus vectors are being explored for gene delivery in CF.

Purpose of the Study:

• To evaluate the safety and efficacy of an adenovirus vector (Ad(GV)CFTR.10) for CFTR gene transfer.
• To assess dose-dependency and duration of CFTR expression in CF airway epithelium.
• To investigate the impact of repeated vector administration on gene expression.

Main Methods:

• Adenovirus vector Ad(GV)CFTR.10 administered via endobronchial spray to individuals with CF.
• Doses ranged from 3 x 10^6 to 2 x 10^9 PFU over 9 months.
• CFTR mRNA levels (vector-derived vs. endogenous) measured pre-therapy and at 3 and 30 days post-therapy.

Main Results:

• The Ad vector strategy was found to be safe.
• Vector-derived CFTR cDNA expression was dose-dependent after initial administration.
• Expression levels exceeded 5% of endogenous CFTR mRNA at higher doses but were transient (<30 days).
• Second administration yielded expression at intermediate doses; third administration showed no expression.
• Lack of sustained expression did not correlate with anti-adenovirus antibodies.

Conclusions:

• Adenovirus vectors can deliver CFTR cDNA to CF airway epithelium, offering potential protection.
• Expression is transient and diminishes with repeated administration.
• Unknown mechanisms limit the efficacy of repeated adenovirus vector administration for sustained CFTR expression.