A phase I study of aerosolized administration of tgAAVCF to cystic fibrosis subjects with mild lung disease

Hum Gene Ther. 2001 Oct 10;12(15):1907-16. doi: 10.1089/104303401753153956.


Cystic fibrosis (CF) is one of the most common autosomal recessive disorders in North America, leading to significant morbidity and early mortality. The defect in the cystic fibrosis transmembrane conductance regulator protein (CFTR) function can be corrected in vitro by gene replacement with a wild-type gene. A Phase I, single administration, dose escalation trial was designed and executed to assess safety and delivery of tgAAVCF, an adeno-associated virus (AAV) vector encoding the human CFTR cDNA, by nebulization to the lungs of CF subjects. Four cohorts of three subjects each were administered increasing doses of the study agent, beginning with 10(10) DNase-resistant particles (DRP) and escalating in log increments up to 10(13) DRP. Sequential bronchoscopies were performed to gather analytical samples throughout the study. All 12 subjects completed the study. There were a total of 242 adverse events (AEs), six of which were defined as serious and three of which were defined as possibly being related to the study drug. A clear dose-response relationship was observed in vector gene transfer. A maximum of 0.6 and 0.1 vector copies per brushed cell were observed 14 days and 30 days, respectively, following nebulization of 10(13) DRP tgAAVCF, and this declined to nearly undetectable levels by day 90. Vector gene transfer was evenly distributed throughout the fourth airway generation following single-dose administration. RNA-specific PCR did not detect vector-derived mRNA. This Phase I trial shows that aerosolized tgAAVCF is safe and widely delivered to the proximal airways of CF subjects by nebulization.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I

MeSH terms

  • Adult
  • Alleles
  • Cells, Cultured
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis / therapy*
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
  • Cytokines / metabolism
  • DNA, Complementary / metabolism
  • Dependovirus / genetics
  • Dose-Response Relationship, Drug
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Gene Transfer Techniques*
  • Genetic Therapy / adverse effects*
  • Genetic Vectors
  • HeLa Cells
  • Humans
  • Immunohistochemistry
  • Lung / physiology
  • Lung Diseases / therapy*
  • Male
  • Mutation
  • Nebulizers and Vaporizers
  • Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Time Factors


  • CFTR protein, human
  • Cytokines
  • DNA, Complementary
  • Cystic Fibrosis Transmembrane Conductance Regulator