Acute responses of non-human primates to airway delivery of an adenovirus vector containing the human cystic fibrosis transmembrane conductance regulator cDNA. Academic Article uri icon

Overview

MeSH

  • Administration, Intranasal
  • Animals
  • Antibodies, Viral
  • Base Sequence
  • Bronchi
  • Bronchoalveolar Lavage Fluid
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Drug Administration Routes
  • Female
  • Humans
  • Inflammation
  • Lung
  • Macaca mulatta
  • Male
  • Molecular Sequence Data
  • Polymerase Chain Reaction
  • Safety

MeSH Major

  • Adenoviruses, Human
  • DNA, Complementary
  • Defective Viruses
  • Gene Transfer Techniques
  • Genetic Vectors
  • Membrane Proteins
  • Recombinant Fusion Proteins

abstract

  • Recombinant human adenovirus (Ad) vectors are leading candidates for human gene therapy for cystic fibrosis (CF) based on demonstration of efficient transfer of exogenous genes to rodent respiratory epithelium in vivo and human respiratory cells in vitro. The safety of Ad-mediated gene transfer to the respiratory epithelium and acute (up to 21 days) clinical responses to airway delivery of a replication-deficient recombinant, E1-, E3- Ad type 5-based vector containing the human cystic fibrosis transmembrane conductance regulator cDNA (AdCFTR) were evaluated in rhesus monkeys. Airway delivery of an Ad vector with the lacZ marker gene demonstrated beta-galactosidase expression in epithelial cells. Animals administered intratracheal AdCFTR demonstrated human CFTR cDNA expression in airway epithelial cells. Animals administered AdCFTR intranasal, and 24 hr later, intrabronchial [2 x 10(7) to 5 x 10(10) plaque-forming units (pfu), n = 12], in a fashion similar to a proposed human protocol, or only intrabronchial (10(11) pfu, n = 3), had no significant changes in clinical parameters compared to vehicle controls (n = 6). Microscopic analysis of the lung by necropsy or bronchoalveolar lavage demonstrated a dose-dependent increase in inflammatory cells, primarily lymphocytes, in the area where AdCFTR was delivered, which persisted for at least 2 months in some animals. Serum anti-Ad type 5 neutralizing antibody titers did not rise and shed Ad was not detected. The presence of AdCFTR DNA, analyzed by the polymerase chain reaction (PCR), was not detected in organs outside the lung. These data demonstrate that AdCFTR is well tolerated in non-human primates, although there is dose-dependent inflammation in the lung not clinically apparent.(ABSTRACT TRUNCATED AT 250 WORDS)

publication date

  • July 1994

has subject area

  • Adenoviruses, Human
  • Administration, Intranasal
  • Animals
  • Antibodies, Viral
  • Base Sequence
  • Bronchi
  • Bronchoalveolar Lavage Fluid
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • DNA, Complementary
  • Defective Viruses
  • Drug Administration Routes
  • Female
  • Gene Transfer Techniques
  • Genetic Vectors
  • Humans
  • Inflammation
  • Lung
  • Macaca mulatta
  • Male
  • Membrane Proteins
  • Molecular Sequence Data
  • Polymerase Chain Reaction
  • Recombinant Fusion Proteins
  • Safety

Research

keywords

  • Journal Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1089/hum.1994.5.7-821

PubMed ID

  • 7526901

Additional Document Info

start page

  • 821

end page

  • 836

volume

  • 5

number

  • 7