In vivo adenovirus-mediated transfer of human CFTR cDNA to rhesus monkey airway epithelium: efficacy, toxicity and safety.
We have administered replication defective recombinant adenovirus harboring the human CFTR cDNA (Ad.CFTR) to lungs of Rhesus monkeys and assessed toxicity, efficiency of gene transfer and containment of recombinant adenovirus in the lungs. Gene transfer efficiencies, as measured by PCR analysis, were dose-dependent. Administration of low dose Ad.CFTR [1.5 x 10(7) plaque forming units (p.f.u.)] was not accompanied by any clinical chemical or histopathological changes. Mild to moderate multifocal perivascular and peribronchial lymphocytic infiltrates were found upon histopathological analysis only after administration of a high dose of recombinant adenovirus, although not accompanied by changes in clinical chemical parameters. Long-term expression (up to 128 days) was found after administration of recombinant adenovirus. Re-challenging of the monkeys treated with high-dose recombinant adenovirus resulted again in gene transfer at all levels of lungs and airways, without being accompanied by additional histopathological changes. Circulating anti-adenovirus antibodies were elicited. Animals treated with high-dose adenovirus secreted virus in pharynx and faeces for maximally 2 and 4 days after administration, respectively. These results show that recombinant adenovirus can be used for efficient delivery of genes into primate airway epithelium without signs of severe toxicity.
Bout
A
A
IntroGene BV, Rijswijk, The Netherlands.
Imler
J L
JL
Schultz
H
H
Perricaudet
M
M
Zurcher
C
C
Herbrink
P
P
Valerio
D
D
Pavirani
A
A
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D003550:Cystic Fibrosis / Q000235:genetics / Q000628:therapy; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics*; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques / Q000009:adverse effects; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D008969:Molecular Sequence Data; D011995:Recombination, Genetic; D012137:Respiratory System / Q000378:metabolism / Q000473:pathology; D012449:Safety; D013997:Time Factors
C505032:CFTR protein, human; D017931:DNA Primers; D018076:DNA, Complementary; D019005:Cystic Fibrosis Transmembrane Conductance Regulator