Biological response of nonhuman primates to long-term repeated lung exposure to Ad2/CFTR-2.
We have assessed the safety and efficacy of repeated adenovirus vector administration by exposing the left caudal lung lobe of rhesus monkeys to as many as 17 exposures of Ad2/CFTR-2. After nine doses of either 3 x 10(9) or 3 x 10(10) infectious units, the monkeys were free of adverse effects as assessed by thoracic radiographs, CBCs, clinical chemistries, arterial blood gases, and physical and clinical signs. In some animals elevated protein levels and increased numbers of cells were recovered in bronchoalveolar lavage (BAL), and in all animals there were increased proportions of lymphocytes in the BAL. After 11 doses, two animals were killed. In the lower dose animal (3 x 10(9) IU), there was little histopathology evident. In the higher dose animal (3 x 10(10) IU), histopathology was largely confined to a focal fibrotic lesion that may have been associated with treatment. At the tenth exposure, the dose was increased to 6 x 10(10) or 3 x 10(11) IU. There was evidence of lung injury by thoracic radiographs after two additional exposures and an increase in protein and number of cells in the BAL. The animals were still free of evidence of adverse effects by other parameters, but histopathologic changes were noted upon death. After 15 or 17 doses, three animals were instilled with Ad2/beta gal-2 and killed 3 days later. These animals had greatly reduced levels of transgene expression when compared with controls.
St George
J A
JA
Genzyme Corporation, Framingham, MA 01701-9322, USA.
Pennington
S E
SE
Kaplan
J M
JM
Peterson
P A
PA
Kleine
L J
LJ
Smith
A E
AE
Wadsworth
S C
SC
D000260:Adenoviruses, Human / Q000235:genetics* / Q000276:immunology; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D003550:Cystic Fibrosis / Q000276:immunology / Q000628:therapy*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004247:DNA / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000009:adverse effects*; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D007958:Leukocyte Count; D008168:Lung / Q000276:immunology / Q000473:pathology*; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology; D008253:Macaca mulatta; D008297:Male; D009504:Neutrophils / Q000276:immunology; D016133:Polymerase Chain Reaction / Q000379:methods; D012333:RNA, Messenger / Q000032:analysis
C505032:CFTR protein, human; D012333:RNA, Messenger; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D004247:DNA