Evaluation of the Duration of Human Factor VIII Expression in Nonhuman Primates After Systemic Delivery of an Adenoviral Vector
- 20 July 2002
- journal article
- research article
- Published by Mary Ann Liebert Inc in Human Gene Therapy
- Vol. 13 (11) , 1331-1336
- https://doi.org/10.1089/104303402760128559
Abstract
An E1/E2a/E3-deficient adenoviral vector encoding an epitope-tagged (flagged) human factor VIII (FVIII) cDNA was delivered systemically to four cynomolgus monkeys. Analysis of liver biopsy samples revealed the presence of vector DNA at all points in the study (day 7, 28, and 56), with vector copy number declining approximately 10-fold between day 7 and day 56. Immunoprecipitation/Western analyses detected human flagged FVIII in the plasma of all monkeys and expression persisted for 14–28 days. Peak plasma FVIII levels ranged from 50 to 100 ng/ml. Bethesda assays revealed no inhibitor in two animals, the development of a low-level transient inhibitor in one animal, and an inhibitor titer that continued to increase for the duration of the study in one animal. Other treatment-related changes included modest increases in liver enzymes, an increase in interleukin-6 (IL-6) levels, and a transient decrease in platelets in all four animals. These data indicate that early generation adenoviral vectors do not support the long-term expression of FVIII in nonhuman primates.Keywords
This publication has 26 references indexed in Scilit:
- Assessment of Adenoviral Vector Safety and Toxicity: Report of the National Institutes of Health Recombinant DNA Advisory CommitteeHuman Gene Therapy, 2002
- Lethal Toxicity, Severe Endothelial Injury, and a Threshold Effect with High Doses of an Adenoviral Vector in BaboonsHuman Gene Therapy, 2002
- Adenovirus-Mediated Factor VIII Gene Expression Results in Attenuated Anti-Factor VIII-Specific Immunity in Hemophilia A Mice Compared with Factor VIII Protein InfusionHuman Gene Therapy, 2001
- Partial Correction of Murine Hemophilia A with Neo-Antigenic Murine Factor VIIIHuman Gene Therapy, 2000
- Adenoviral Vector-Mediated Expression of Physiologic Levels of Human Factor VIII in Nonhuman PrimatesHuman Gene Therapy, 1999
- In vivo evaluation of a novel epitope‐tagged human factor VIII‐encoding adenoviral vectorHaemophilia, 1999
- In Vivo Evaluation of an Adenoviral Vector Encoding Canine Factor VIII: High-Level, Sustained Expression in Hemophiliac MiceHuman Gene Therapy, 1999
- Cytokine Regulation of Hepatic Stellate Cells in Liver FibrosisAlcohol, Clinical and Experimental Research, 1999
- Cytokines and FibrogenesisSeminars in Liver Disease, 1999
- In VivoGene Delivery and Expression of Physiological Levels of Functional Human Factor VIII in MiceHuman Gene Therapy, 1995