MODIFICATION OF NASAL EPITHELIAL POTENTIAL DIFFERENCES OF INDIVIDUALSWITH CYSTIC-FIBROSIS CONSEQUENT TO LOCAL-ADMINISTRATION OF A NORMAL CFTR CDNA ADENOVIRUS GENE-TRANSFER VECTOR

Mutations in the cystic fibrosis transmembrane conductance regulator g ene (CFTR) manifest on the nasal epithelial surface of individuals wit h cystic fibrosis (CF) by Na+ hyperabsorption and diminished beta-agon ist-induced Cl- conductance, resulting in an abnormal bioelectric phen otype across the nasal epithelium. A clinical trial was conducted to d etermine if a replication-deficient, recombinant adenovirus vector con taining a normal copy of the CFTR cDNA (AdCFTR) could, when administer ed to the nasal epithelium, correct the abnormal bioelectric phenotype . Nine individuals with CF received 2 x 10(5) to 2 x 10(8.5) plaque fo rming units of AdCFTR to the epithelium of one nostril. Measurements m ade included: baseline electrical potential difference (PD) between th e surface of the nasal epithelium and the interstitial fluid, change i n PD in response to amiloride, which inhibits apical Naf channels, and change in PD in response to isoproterenol in a low Cl- solution, a me asure of cAMP-regulated Cl- conductance. The functional integrity of t he 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 untr eated nostril. On the average, in the treated nostril over 2 weeks aft er the local administration of the adenovirus vector compared to measu rements made in the same nostril before treatment, baseline PD decreas ed 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 Cl- and isoproterenol increased toward norm al (-4.5 +/- 1.5 to -9.1 +/- 2.1, p 0.05). There were no changes in re sponse to ATP (-15.3 +/- 2.7 to -15.8 +/- 1.9, p = 0.39), suggesting t hat the epithelium remained functionally intact. Importantly, there we re no significant changes in measurements made in the untreated nostri l. While limited to the nasal epithelium, these data suggest an adenov irus vector can safely deliver sufficient CFTR cDNA function to improv e the abnormal CF bioelectric phenotype.