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

Steven L. Brody, Mark Metzger, Claire Danel, Melissa A. Rosenfeld, Ronald Crystal

Research output: Contribution to journalArticle

136 Citations (Scopus)

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 (Ad-CFTR) were evaluated in rhesus monkeys. Airway delivery of an Ad vector with the lacZ marker gene demonstrated β-galactosidase expression in epithelial cells. Animals administered intratracheal Ad-CFTR demonstrated human CFTR cDNA expression in airway epithelial cells. Animals administered Ad-CFTR intranasal, and 24 hr later, intrabronchial [2 x 107 to 5 x 1010 plaque-forming units (pfu), n= 12], in a fashion similar to a proposed human protocol, or only intrabronchial (1011 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 Ad-CFTR 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 Ad-CFTR DNA, analyzed by the polymerase chain reaction (PCR), was not detected in organs outside the lung. These data demonstrate that Ad-CFTR is well tolerated in non-human primates, although there is dose-dependent inflammation in the lung not clinically apparent. This suggests that delivery of Ad vectors for human gene therapy may be dose limited.

Original languageEnglish
Pages (from-to)821-836
Number of pages16
JournalHuman Gene Therapy
Volume5
Issue number7
DOIs
Publication statusPublished - 1 Jan 1994
Externally publishedYes

Fingerprint

Cystic Fibrosis Transmembrane Conductance Regulator
Adenoviridae
Primates
Complementary DNA
Human Adenoviruses
Respiratory Mucosa
Bronchoalveolar Lavage
Genetic Therapy
Epithelial Cells
Galactosidases
Lac Operon
DNA-Directed DNA Polymerase
Neutralizing Antibodies
Macaca mulatta
Cystic Fibrosis
Genes
Rodentia
Pneumonia
Lymphocytes

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Acute responses of non-human primates to airway delivery of an adenovirus vector containing the human cystic fibrosis transmembrane conductance regulator cDNA. / Brody, Steven L.; Metzger, Mark; Danel, Claire; Rosenfeld, Melissa A.; Crystal, Ronald.

In: Human Gene Therapy, Vol. 5, No. 7, 01.01.1994, p. 821-836.

Research output: Contribution to journalArticle

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