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

Overview

MeSH

  • Adenoviridae
  • Adolescent
  • Adult
  • Cohort Studies
  • DNA, Complementary
  • Dose-Response Relationship, Drug
  • Epithelium
  • Female
  • Genetic Vectors
  • Humans
  • Male
  • Middle Aged
  • Models, Genetic
  • Polymerase Chain Reaction
  • RNA, Messenger
  • Recombination, Genetic
  • Time Factors

MeSH Major

  • Bronchi
  • Cystic Fibrosis
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Genetic Therapy
  • Trachea

abstract

  • We sought to evaluate the ability of an E1(-), E3(-) adenovirus (Ad) vector (Ad(GV)CFTR.10) to transfer the normal human cystic fibrosis transmembrane conductance regulator (CFTR) cDNA to the airway epithelium of individuals with cystic fibrosis (CF). We administered Ad(GV)CFTR.10 at doses of 3 x 10(6) to 2 x 10(9) plaque-forming units over 9 months by endobronchial spray to 7 pairs of individuals with CF. Each 3-month cycle, we measured vector-derived versus endogenous CFTR mRNA in airway epithelial cells prior to therapy, as well as 3 and 30 days after therapy. The data demonstrate that (a) this strategy appears to be safe; (b) after the first administration, vector-derived CFTR cDNA expression in the CF airway epithelium is dose-dependent, with greater than 5% endogenous CFTR mRNA levels at the higher vector doses; (c) expression is transient, lasting less than 30 days; (d) expression can be achieved with a second administration, but only at intermediate doses, and no expression is observed with the third administration; and (e) the progressive lack of expression with repetitive administration does not closely correlate with induction of systemic anti-Ad neutralizing antibodies. The major advantage of an Ad vector is that it can deliver sufficient levels of CFTR cDNA to the airway epithelium so that CFTR expression protects the lungs from the respiratory manifestations of CF. However, this impressive level of expression is linked to the challenging fact that expression is limited in time. Although this can be initially overcome by repetitive administration, unknown mechanisms eventually limit this strategy, and further repetitive administration does not lead to repetitive expression.

publication date

  • November 1999

has subject area

  • Adenoviridae
  • Adolescent
  • Adult
  • Bronchi
  • Cohort Studies
  • Cystic Fibrosis
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • DNA, Complementary
  • Dose-Response Relationship, Drug
  • Epithelium
  • Female
  • Genetic Therapy
  • Genetic Vectors
  • Humans
  • Male
  • Middle Aged
  • Models, Genetic
  • Polymerase Chain Reaction
  • RNA, Messenger
  • Recombination, Genetic
  • Time Factors
  • Trachea

Research

keywords

  • Clinical Trial
  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC409826

Digital Object Identifier (DOI)

  • 10.1172/JCI7935

PubMed ID

  • 10545523

Additional Document Info

start page

  • 1245

end page

  • 1255

volume

  • 104

number

  • 9