The Mesenchymal Stem Cells Derived from Transgenic Mice Carrying Human Coagulation Factor VIII Can Correct Phenotype in Hemophilia A Mice

Qing Wang^a,
Xiuli Gong^{a, b},
Zhijuan Gong^{a, b},
Xiaoyie Ren^a,
Zhaorui Ren^{a, b},
Shuzhen Huang^{a, b},
Yitao Zeng^{a, b
, ,}

a.
Shanghai Institute of Medical Genetics, Children's Hospital of Shanghai, Shanghai Jiao Tong University School of Medicine, Shanghai 200040, China
b.
Key Laboratory of Embryo Molecular Biology, Ministry of Health & Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai 200040, China

More Information

Corresponding author: E-mail address: ytzeng@stn.sh.cn (Yitao Zeng)

摘要

- /
- /
- /
- /
Abstract: Hemophilia A (HA) is an inherited X-linked recessive bleeding disorder caused by coagulant factor VIII (FVIII) deficiency. Previous studies showed that introduction of mesenchymal stem cells (MSCs) modified by FVIII-expressing retrovirus may result in phenotypic correction of HA animals. This study aimed at the investigation of an alternative gene therapy strategy that may lead to sustained FVIII transgene expression in HA mice. B-domain-deleted human FVIII (hFVIIIBD) vector was microinjected into single-cell embryos of wild-type mice to generate a transgenic mouse line, from which hFVIIIBD-MSCs were isolated, followed by transplantation into HA mice. RT-PCR and real-time PCR analysis demonstrated the expression of hFVIIIBD in multi-organs of recipient HA mice. Immunohistochemistry showed the presence of hFVIIIBD positive staining in multi-organs of recipient HA mice. ELISA indicated that plasma hFVIIIBD level in recipient mice reached its peak (77 ng/mL) at the 3rd week after implantation, and achieved sustained expression during the 5-week observation period. Plasma FVIII activities of recipient HA mice increased from 0% to 32% after hFVIIIBD-MSCs transplantation. APTT (activated partial thromboplastin time) value decreased in hFVIIIBD-MSCs transplanted HA mice compared with untreated HA mice (45.5 s vs. 91.3 s). Our study demonstrated an effective phenotypic correction in HA mice using genetically modified MSCs from hFVIIIBD transgenic mice.
- Hemophilia A /
- MSCs /
- FVIII /
- Transgenic mouse /
- Gene therapy

HTML全文

参考文献(53)

[1]	Aggarwal, S., Pittenger, M.F. Human mesenchymal stem cells modulate allogeneic immune cell responses Blood, 105 (2005),pp. 1815-1822
[2]	Arruda, V.R. Toward gene therapy for hemophilia A with novel adenoviral vectors: successes and limitations in canine models J. Thromb. Haemost., 4 (2006),pp. 1215-1217
[3]	Becker, S., Simpson, J.C., Pepperkok, R. et al. Confocal microscopy analysis of native, full length and B-domain deleted coagulation factor VIII trafficking in mammalian cells Thromb. Haemost., 92 (2004),pp. 23-35
[4]	Brown, B.D., Shi, C.X., Rawle, F.E. et al. Factors influencing therapeutic efficacy and the host immune response to helper-dependent adenoviral gene therapy in hemophilia A mice J. Thromb. Haemost., 2 (2004),pp. 111-118
[5]	Chuah, M.K., VanDamme, A., Zwinnen, H. et al. Long-term persistence of human bone marrow stromal cells transduced with factor VIII-retroviral vectors and transient production of therapeutic levels of human factor VIII in nonmyeloablated immunodeficient mice Hum. Gene Ther., 11 (2000),pp. 729-738
[6]	Chuah, M.K., Collen, D., VandenDriessche, T. Clinical gene transfer studies for hemophilia A Semin. Thromb. Hemost., 30 (2004),pp. 249-256
[7]	Colletti, E.J., Airey, J.A., Liu, W. et al. Generation of tissue-specific cells by MSC does not require fusion or donor-to-host mitochondrial/membrane transfer Stem Cell Res., 2 (2009),pp. 125-138
[8]	da Silva Meirelles, L., Chagastelles, P.C., Nardi, N.B. Mesenchymal stem cells reside in virtually all post-natal organs and tissues J. Cell Sci., 119 (2006),pp. 2204-2213
[9]	Deans, R.J., Moseley, A.B. Mesenchymal stem cells: biology and potential clinical uses Exp. Hematol., 28 (2000),pp. 875-884
[10]	Doering, C.B. Retroviral modification of mesenchymal stem cells for gene therapy of hemophilia Methods Mol. Biol., 433 (2008),pp. 203-212
[11]	Doering, C.B., Spencer, H.T. Advancements in gene transfer-based therapy for hemophilia A Expert Rev. Hematol., 2 (2009),pp. 673-683
[12]	Follenzi, A., Benten, D., Novikoff, P. et al. Transplanted endothelial cells repopulate the liver endothelium and correct the phenotype of hemophilia A mice J. Clin. Invest., 118 (2008),pp. 935-945
[13]	Gangadharan, B., Parker, E.T., Ide, L.M. et al. High-level expression of porcine factor VIII from genetically modified bone marrow-derived stem cells Blood, 107 (2006),pp. 3859-3864
[14]	Gan, S.U., Kon, O.L., Calne, R.Y. Genetic engineering for haemophilia A Exp. Opin. Biol. Ther., 6 (2006),pp. 1023-1030
[15]	Hacein-Bey-Abina, S., Von Kalle, C., Schmidt, M. et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCIDX1 Science, 302 (2003),pp. 415-419
[16]	Hacein-Bey-Abina, S., Garrigue, A., Wang, G.P. et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1 J. Clin. Invest., 118 (2008),pp. 3132-3142
[17]	Hough, C., Lillicrap, D. Gene therapy for hemophilia: an imperative to succeed J. Thromb. Haemost., 3 (2005),pp. 1195-1205
[18]	Huang, Z., Yan, J.B., Huang, Y. et al. High expression of human FIX (hFIX) in transgenic mice directed by goat beta-casein gene promoter Acta Genet. Sin., 29 (2002),pp. 206-211
[19]	Hu, C., Cela, R.G., Suzuki, M. et al. Neonatal help-dependent adenoviral vector gene therapy mediates correction of hemophilia A and tolerance to human factor VIII Proc. Natl. Acad. Sci. USA, 108 (2011),pp. 2082-2087
[20]	Ide, L.M., Gangadharan, B., Chiang, K.Y. et al. Hematopoietic stem-cell gene therapy of hemophilia A incorporating a porcine factor VIII transgene and nonmyeloablative conditioning regimens Blood, 110 (2007),pp. 2855-2863
[21]	Kang, Y., Xie, L., Tran, D.T. et al. Blood, 106 (2005),pp. 1552-1558
[22]	Kootstra, N.A., Matsumura, R., Verma, I.M. Efficient production of human FVIII in hemophilic mice using lentiviral vectors Mol. Ther., 7 (2003),pp. 623-631
[23]	Kumaran, V., Benten, D., Follenzi, A. et al. Transplantation of endothelial cells corrects the phenotype in hemophilia A mice J. Thromb. Haemost., 3 (2005),pp. 2022-2031
[24]	Le Blanc, K., Tammik, L., Sundberg, B. et al. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex Scand. J. Immunol., 57 (2003),pp. 11-20
[25]	Le Blanc, K., Ringden, O. Immunobiology of human mesenchymal stem cells and future use in hematopoietic stem cell transplantation Biol. Blood Marrow Transplant., 11 (2005),pp. 321-334
[26]	Lin, Y., Chang, L., Solovey, A. et al. Use of blood outgrowth endothelial cells for gene therapy for hemophilia A Blood, 99 (2002),pp. 457-462
[27]	Liu, H., Kemeny, D.M., Heng, B.C. et al. The immunogenicity and immunomodulatory function of osteogenic cells differentiated from mesenchymal stem cells J. Immunol., 176 (2006),pp. 2864-2871
[28]	Lozier, J.N., Metzger, M.E., Donahue, R.E. et al. Adenovirus-mediated expression of human coagulation factor IX in the rhesus macaque is associated with dose-limiting toxicity Blood, 94 (1999),pp. 3968-3975
[29]	Manno, C.S., Pierce, G.F., Arruda, V.R. et al. Successful transduction of liver in hemophilia by AAV factor IX and limitations imposed by the host immune response Nat. Med., 12 (2006),pp. 342-347
[30]	Matsui, H., Shibata, M., Brown, B. et al. Stem Cells, 25 (2007),pp. 2660-2669
[31]	Miller, D.G., Trobridge, G.D., Petek, L.M. et al. Large-scale analysis of adeno-associated virus vector integration sites in normal human cells J. Virol., 79 (2005),pp. 11434-11442
[32]	Moayeri, M., Ramezani, A., Morgan, R.A. et al. Sustained phenotypic correction of hemophilia a mice following oncoretroviral-mediated expression of a bioengineered human factor VIII gene in long-term hematopoietic repopulating cells Mol. Ther., 10 (2004),pp. 892-902
[33]	Modlich, U., Bohne, J., Schmidt, M. et al. Cell-culture assays reveal the importance of retroviral vector design for insertional genotoxicity Blood, 108 (2006),pp. 2545-2553
[34]	Modlich, U., Schambach, A., Brugman, M.H. et al. Leukemia induction after a single retroviral vector insertion in Evi1 or Prdm16 Leukemia, 22 (2008),pp. 1519-1528
[35]	Ott, M.G., Schmidt, M., Schwarzwaelder, K. et al. Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation by MDS1-EVI1, PRDM16 or SETBP1 Nat. Med., 12 (2006),pp. 401-409
[36]	Porada, C.D., Almeida-Porada, G. Mesenchymal stem cells as therapeutics and vehicles for gene and drug delivery Adv. Drug Deliv. Rev., 62 (2010),pp. 1156-1166
[37]	Porada, C.D., Sanada, C., Kuo, C.J. et al. Phenotypic correction of hemophilia A in sheep by postnatal intraperitoneal transplantation of FVIII-expressing MSC Exp. Hematol., 39 (2011),pp. 1124-1135
[38]	Powell, J.S., Ragni, M.V., , Lusher, J.M. et al. Blood, 102 (2003),pp. 2038-2045
[39]	Ramezani, A., Hawley, T.S., Hawley, R.G. Reducing the genotoxic potential of retroviral vectors Methods. Mol. Biol., 434 (2008),pp. 183-203
[40]	Ramezani, A., Hawley, R.G. Correction of murine hemophilia A following nonmyeloablative transplantation of hematopoietic stem cells engineered to encode an enhanced human factor VIII variant using a safety-augmented retroviral vector Blood, 114 (2009),pp. 526-534
[41]	Sarkar, R., Gao, G.P., Chirmule, N. et al. Partial correction of murine hemophilia A with nonantigenic murine factor VIII Hum. Gene Ther., 11 (2000),pp. 881-894
[42]	Sanada, C., Kuo, C.J., Colletti, E.J. et al. Mesenchymal stem cells contribute to endogenous FVIII:c production J. Cell Physiol., 228 (2013),pp. 1010-1016
[43]	Themis, M., Waddington, S.N., Schmidt, M. et al. Oncogenesis following delivery of a nonprimate lentiviral gene therapy vector to fetal and neonatal mice Mol. Ther., 12 (2005),pp. 763-771
[44]	Thorrez, L., VandenDriessche, T., Collen, D. et al. Preclinical gene therapy studies for hemophilia using adenoviral vectors Semin. Thromb. Hemost., 30 (2004),pp. 173-183
[45]	Van Damme, A., Chuah, M.K., Collen, D. et al. Onco-retroviral and lentiviral vector-based gene therapy for hemophilia: preclinical studies Semin. Thromb. Hemost., 30 (2004),pp. 185-195
[46]	Van Damme, A., Thorrez, L., Ma, L. et al. Efficient lentiviral transduction and improved engraftment of human bone marrow mesenchymal cells Stem Cells, 24 (2006),pp. 896-907
[47]	VandenDriessche, T., Collen, D., Chuah, M.K. Viral vector-mediated gene therapy for hemophilia Curr. Gene Ther., 1 (2001),pp. 301-315
[48]	VandenDriessche, T., Collen, D., Chuah, M.K. Biosafety of onco-retroviral vectors Curr. Gene Ther., 3 (2003),pp. 501-515
[49]	Wang, W., Merchlinsky, M., Inman, J. et al. Identification of a novel immunodominant cytotoxic T lymphocyte epitope derived from human factor VIII in a murine model of hemophilia A Thromb. Res., 116 (2005),pp. 335-344
[50]	Wion, K.L., Kelly, D., Summerfield, J.A. et al. Distribution of factor VIII mRNA and antigen in human liver and other tissues Nature, 317 (1985),pp. 726-729
[51]	Yadav, N., Kanjirakkuzhiyil, S., Kumar, S. et al. The therapeutic effect of bone marrow-derived liver cells in the phenotypic correction of murine hemophilia A Blood, 114 (2009),pp. 4552-4561
[52]	Yadav, N., Kanjirakkuzhiyil, S., Ramakrishnan, M. et al. Factor VIII can be synthesized in hemophilia A mice liver by bone marrow progenitor cell-derived hepatocytes and sinusoidal endothelial cells Stem Cells Dev., 21 (2012),pp. 110-120
[53]	Yin, J., Wang, H.L., Wang, X.F. et al. Non-viral vector mediating human coagulation factor VIII gene expression in mouse 32D cell line J. Exp. Hematol., 12 (2004),pp. 721-725