Complete and sustained phenotypic correction of hemophilia B in mice following hepatic gene transfer of a high-expressing human factor IX plasmid |
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| Authors: | X Ye K R Loeb † D W Stafford ‡ A R Thompson C H Miao |
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| Institution: | Departments of Pediatrics and Medicine, University of Washington, Puget Sound Blood Center, WA, USA;;Fred Hutchinson Cancer Research Center, Seattle, WA, USA;and;Department of Biology, University of North Carolina, Chapel Hill, NC, USA |
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| Abstract: | Summary. Therapeutic correction of hemophilia B was achieved by rapid infusion of a large-volume solution containing a high-expressing human factor IX (hFIX) plasmid into the tail vein of hemophilia B mice. hFIX circulated at therapeutic levels (1–5 µg mL−1) in all animals for more than 1 year as determined by both species-specific antigen assay and an activated partial thromboplastin time (APTT)-based clotting assay. There was acute, transient hepatic tissue damage by the infusion procedure and no significant inhibitory anti-hFIX antibodies developed. No bleeding episode was observed during or after treatment. Immunohistochemical studies indicated that the hFIX gene was exclusively expressed in hepatocytes, and that transduced cells had readily detectable hFIX protein at 4 h postinfusion, and stainable protein persisted for up to 1 year. Repeated infusions of hFIX plasmids boosted the hFIX expression to higher levels. These results demonstrate that hemophilia B can be treated by gene transfer of naked hFIX plasmids. |
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| Keywords: | factor IX gene therapy hemophilia hepatic gene expression naked DNA transfer |
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