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Increase in therapeutic effects and therapeutic window of hepatocyte xenotransplantation in hemophilia B mice with a safe pretreatment strategy coupled with genetically engineered donor cells
Author(s) -
Hsu YuChen,
Yang ShuJhu,
Chen KuangYen,
Yeh ChiuWen,
Huang YuJen,
Yu IShing,
Wu YaoMing,
Lin ShuWha
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.924.1
Subject(s) - xenotransplantation , transplantation , hepatocyte , coagulation , genetic enhancement , medicine , hepatocyte growth factor , factor ix , cancer research , immunology , liver transplantation , cell , pharmacology , chemistry , gene , receptor , biochemistry , in vitro
Xenotransplantation of hepatocytes has extensive value for patients with liver‐based metabolic defects, coagulation disorders and liver failure. Since the low efficiency of integration of transplanted hepatocytes into recipient livers currently limits clinical applications, a safe strategy to improve donor hepatocyte engraftment can be expected to widen the clinical use of cell therapy in liver disease. Hemophilia B is considered to be a good disease model for developing cell therapy because it is caused by a single protein (coagulation factor IX, FIX) deficiency, and the quality of patients’ lives can be dramatically improved through a slight increase in therapeutic coagulation protein. In our previous study, we observed an enhanced engraftment of intrasplenically injected cancer cells into the liver of a specific mouse strain due to its narrowed sinusoids, and therefore we suspected that narrow sinusoids may enhance the efficiency of hepatocyte transplantation. Here, we developed a strategy by pre‐administration of the antibody (anti‐X) to decrease the hepatic sinusoidal diameter in the mice and applied this strategy to improve the therapeutic effect of hepatocyte transplantation for hemophilia B. We observed that the amount of transplanted cells was nearly 2 times more in the anti‐X pretreated mice than in the WT livers at all time points up until one month. Furthermore, we coupled the anti‐X pretreatment strategy with a bioengineered human FIX with augmented specific activity, named FIX‐Triple, to improve the effects and therapeutic window of hepatocyte transplantation in Hemophilia B mice. After intravenous infusion of an adeno‐associated viral vector encoding FIX‐wildtype or FIX‐Triple, the donor hepatocytes were isolated and transplanted into the hemophilia B mice with anti‐X or control IgG pretreatment, then the haemostatic protection of the hepatocyte transplantation was evaluated on day 25 after transplantation. Compared with the control IgG pretreated mice receiving FIX‐wildtype expressing hepatocyte transplantation, the anti‐X pretreatment strategy coupled with FIX‐Triple‐donor increased the FIX clotting activity more than 5‐fold and dramatically decreased the bleeding time and total blood volume loss in the recipient hemophilia B mice. Our results demonstrated that the antibody‐pretreatment strategy coupled with the high activity FIX variant FIX‐Triple resulted in significant improvement in the haemophilic phenotype after hepatocyte transplantation.