Safety and efficacy of repetitive adenovirus-mediated transfer of CFTR cDNA to airway epithelia of primates and cotton rats

Gene therapy for cystic fibrosis (CF) will require the safe transfer of CFTR cDNA to airway epithelia in vivo. We showed previously that a recombinant adenovirus, Ad2/CFTR-1, expresses CFTR in vitro. As adenovirus rarely integrates, treatment will require repeated vector administration. We applied A...

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Bibliographic Details
Published in:	Nature genetics Vol. 6; no. 1; pp. 75 - 83
Main Authors:	Zabner, Joseph, Petersen, Deanna M, Puga, Aurita P, Graham, Scott M, Couture, Larry A, Keyes, Lynn D, Lukason, Mike J, St. George, Judith A, Gregory, Richard J, Smith, Alan E, Welsh, Michael J
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group 01-01-1994
Subjects:	Adenoviridae - genetics adenovirus Animals Base Sequence Biological and medical sciences Cystic Fibrosis - genetics Cystic Fibrosis - therapy Cystic Fibrosis Transmembrane Conductance Regulator DNA Primers - genetics DNA, Complementary - administration & dosage DNA, Complementary - genetics Epithelium - metabolism Female Gastroenterology. Liver. Pancreas. Abdomen Gene Expression Genetic Therapy - adverse effects Genetic Therapy - methods Genetic Vectors Humans Liver. Biliary tract. Portal circulation. Exocrine pancreas Macaca mulatta Medical sciences Membrane Proteins - genetics Molecular Sequence Data Other diseases. Semiology Polymerase Chain Reaction Primates Respiratory System - metabolism Respiratory System - pathology Safety Sigmodon hispidus Sigmodontinae Adenoviridae Respiratory disease Rodentia Macaca mulatta Gene expression Genetic disease Virus Multiple dose Vertebrata Adenovirus 2 Mucoviscidosis Mammalia Complementary DNA Human adenovirus Primates Simioidea Digestive diseases Mastadenovirus Gene therapy Vector Sigmodon hispidus Pancreatic disease
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Summary:	Gene therapy for cystic fibrosis (CF) will require the safe transfer of CFTR cDNA to airway epithelia in vivo. We showed previously that a recombinant adenovirus, Ad2/CFTR-1, expresses CFTR in vitro. As adenovirus rarely integrates, treatment will require repeated vector administration. We applied Ad2/CFTR-1 to intrapulmonary airway epithelia of cotton rats and nasal epithelia of Rhesus monkeys. In both species we detected CFTR mRNA and protein after repeated administration and in monkeys, protein was detected six weeks after repeat administration. The vector did not replicate and was rapidly cleared. Despite an antibody response, there was no evidence of a local or systemic inflammatory response after repeat administration. These data indicate that repetitive administration of Ad2/CFTR-1 is both safe and efficacious.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	1061-4036 1546-1718
DOI:	10.1038/ng0194-75