Toxicity of a first-generation adenoviral vector in rhesus macaques.
We constructed a first-generation adenovirus vector (AVC3FIX5) that we used to assess the rhesus macaque as a nonhuman primate model for preclinical testing of hemophilia B gene therapy vectors. Although we succeeded in our primary objective of demonstrating expression of human factor IX we encountered numerous toxic side effects that proved to be dose limiting. Following intravenous administration of AVC3FIX5 at doses of 3.4 x 10(11) vector particles/kg to 3.8 x 10(12) vector particles/kg, the animals in our study developed antibodies against human factor IX, and dose-dependent elevations of enzymes specific for liver, muscle, and lung injury. In addition, these animals showed dose-dependent prolongation of clotting times as well as acute, dose-dependent decreases in platelet counts and concomitant elevation of fibrinogen and von Willebrand factor. These abnormalities may be caused by the direct toxic effects of the adenovirus vector itself, or may result indirectly from the accompanying acute inflammatory response marked by elevations in IL-6, a key regulator of the acute inflammatory response. The rhesus macaque may be a useful animal model in which to evaluate mechanisms of adenovirus toxicities that have been encountered during clinical gene therapy trials.
Lozier
Jay N
JN
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. lozier@cber.fda.gov
Csako
Gyorgy
G
Mondoro
Traci H
TH
Krizek
D M
DM
Metzger
Mark E
ME
Costello
Rene
R
Vostal
Jaroslav G
JG
Rick
M E
ME
Donahue
Robert E
RE
Morgan
Richard A
RA
D000260:Adenoviruses, Human / Q000235:genetics*; D000818:Animals; D001772:Blood Cell Count; D003402:Creatine Kinase / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004797:Enzyme-Linked Immunosorbent Assay; D005164:Factor IX / Q000235:genetics* / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000633:toxicity*; D002836:Hemophilia B / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects; D008253:Macaca mulatta; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology; D010974:Platelet Aggregation; D014841:von Willebrand Factor / Q000378:metabolism
D015850:Interleukin-6; D007527:Isoenzymes; D014841:von Willebrand Factor; D005164:Factor IX; D005340:Fibrinogen; D007770:L-Lactate Dehydrogenase; D003402:Creatine Kinase