Modification of Nasal Epithelial Potential Differences of Individuals with Cystic Fibrosis Consequent to Local Administration of a Normal CFTR cDNA Adenovirus Gene Transfer Vector

Abstract

Mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) manifest on the nasal epithelial surface of individuals with cystic fibrosis (CF) by Na⁺ hyperabsorption and diminished β-agonist-induced Cl¯ conductance, resulting in an abnormal bioelectric phenotype across the nasal epithelium. A clinical trial was conducted to determine if a replication-deficient, recombinant adenovirus vector containing a normal copy of the CFTR cDNA (AdCFTR) could, when administered to the nasal epithelium, correct the abnormal bioelectric phenotype. Nine individuals with CF received 2 × 10⁵ to 2 × 10^8.5 plaque forming units of AdCFTR to the epithelium of one nostril. Measurements made included: baseline electrical potential difference (PD) between the surface of the nasal epithelium and the interstitial fluid, change in PD in response to amiloride, which inhibits apical Na⁺ channels, and change in PD in response to isoproterenol in a low Cl¯ solution, a measure of cAMP-regulated Cl¯ conductance. The functional integrity of the epithelium was evaluated by the PD response to ATP. Each individual served as their own control with measurements made in the nostril to be treated before AdCFTR administration, and in the contralateral untreated nostril. On the average, in the treated nostril over 2 weeks after the local administration of the adenovirus vector compared to measurements made in the same nostril before treatment, baseline PD decreased toward normal (–53.3 ± 4.0 to –34.6 ± 3.4, p = 0.01), response to amiloride decreased toward normal (36.9 ± 4.7 to 19.7 ± 3.0, p = 0.02), and response to low CI¯ and isoproterenol increased toward normal (–4.5 ± 1.5 to –9.1 ± 2.1, p = 0.05). There were no changes in response to ATP (–15.3 ± 2.7 to –15.8 ± 1.9, p = 0.39), suggesting that the epithelium remained functionally intact. Importantly, there were no significant changes in measurements made in the untreated nostril. While limited to the nasal epithelium, these data suggest an adenovirus vector can safely deliver sufficient CFTR cDNA function to improve the abnormal CF bioelectric phenotype.

Overview summary

Cystic fibrosis (CF) is a common lethal hereditary disease resulting from mutations in both copies of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR gene product is a cAMP-regulated CI¯ channel expressed on various epithelial surfaces, and mutations within this gene result in abnormal ion transport. CFTR function can be conveniently measured as a potential difference across the nasal epithelial surface, and the CF bioelectric phenotype is characterized by decreased conductance across the epithelium to chloride ions (CI¯) and hyperabsorption of sodium ions (Na⁺). Single administration of a replication-deficient recombinant adenovirus vector containing the normal human CFTR cDNA (AdCFTR) to the nasal epithelium of nine individuals with CF was associated with improvements toward normal values in measurements of Cl¯ and Na⁺ transport across the nasal epithelium over a 2-week period without evidence of epithelial injury. An adenovirus vector can therefore deliver sufficient CFTR cDNA function to improve the abnormal CF biologic phenotype.