Genetic modification of donor hepatocytes improves therapeutic efficacy for hemophilia B in mice
Journal
Cell Transplantation
Journal Volume
19
Journal Issue
9
Pages
1169-1180
Date Issued
2010
Author(s)
Kao C.-Y.
Huang Y.-J.
Yu I.-S.
Lin C.-N.
Abstract
Hepatocyte transplantation (Tx) holds promise for curing genetic liver diseases. However, a limited number of donor hepatocytes can be transplanted into the host liver. Recipient preconditioning and donor cell engineering are under investigation to improve cell engraftment. In theory, genetically engineered cells secreting therapeutic proteins with superior function could compensate for poor engraftment efficiency. We have generated a bioengineered human coagulation factor IX (FIX) with augmented specific activity (named FIX-Triple). The aim of this study was to evaluate therapeutic efficacy of cell therapy using hemophilia B (HB) as a disease model by transplanting FIX-Triple-secreting hepatocytes. The donor hepatocytes were isolated from FIX-Triple knock-in (KI) or FIX-WT (wild-type) KI mice and transplanted intrasplenically into FIX knock-out (KO) mice. FIX-Triple KI recipients exhibited fourfold higher plasma FIX clotting activity than FIX-WT KI recipients. By repeated Txs, the clotting activity of FIX-Triple KI recipients even increased to more than 10% of normal mouse plasma. The engraftment and FIX production efficiencies of transplanted cells were equivalent between the FIX-WT KI and FIX-Triple KI donors. A hemostatic function assay showed that FIX-Triple KI recipients with repeated Txs had more enhanced clot kinetics and a greater maximum rate of thrombus generation than those with a single Tx. Moreover, FIX inhibitors in these recipients rarely developed. In conclusion, hepatocyte Tx with genetically engineered donor cells is an effective therapeutic strategy for HB. All rights reserved. Copyright ? 2010 Cognizant Comm. Corp.
SDGs
Other Subjects
blood clotting factor 9; animal cell; animal experiment; animal model; animal tissue; article; bioengineering; blood clotting; cell isolation; cell therapy; cell transplantation; controlled study; hemophilia B; hemostasis; human; liver cell; male; mouse; nonhuman; priority journal; protein modification; thrombus; Animals; Cell Transplantation; Disease Models, Animal; Factor IX; Gene Expression Regulation; Hemophilia B; Hepatocytes; Humans; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Tissue Engineering; Mus
Type
journal article