Factor IX: Insights from knock-out and genetically engineered mice

 

 Buy Article Permissions and Reprints

Summary

The study of coagulation factors has been rapidly advanced by studies performed in genetically engineered mouse strains. Investigation of factor IX (FIX) has benefited from excellent genedeleted mouse models that recapitulate many of the features of human haemophilia B. Moreover, advanced positional cloning techniques and availability of technology to allow not only knock-out mice, but also knock-in and knock-down mice, provide new opportunities to observe genotype-phenotype and structure-function correlations regarding FIX, as well as the interaction of FIX with inflammatory, immune, and tissue repair systems. In this paper, available FIX knock-out mice and additional haemophilia B mouse models are reviewed specifically in regards to observations these models have facilitated concerning: factor IX gene expression and factor IX protein pharmacokinetics; the role of FIX in haemostasis, thrombosis and wound healing; insights into coagulation FIX arising out of gene therapy applications in haemophilia mouse models; immunology of tolerance or loss of tolerance of FIX and inhibitor antibody formation.

• References

• 1 Manis JP. Knock out, knock in, knock down--genetically manipulated mice and the Nobel Prize. N Engl J Med 2007; 357: 2426-2429.
  CrossrefPubMedGoogle Scholar
• 2 Ovlisen K, Kristensen AT, Tranholm M. In vivo models of haemophilia – status on current knowledge of clinical phenotypes and therapeutic interventions. Haemophilia 2008; 14: 248-259.
  CrossrefPubMedGoogle Scholar
• 3 Rawle FE, Lillicrap D. Preclinical animal models for hemophilia gene therapy: predictive value and limitations. Semin Thromb Hemost 2004; 30: 205-213.
  Article in Thieme ConnectPubMedGoogle Scholar
• 4 Wu SM, Stafford DW, Ware J. Deduced amino acid sequence of mouse blood-coagulation factor IX. Gene 1990; 86: 275-278.
  CrossrefPubMedGoogle Scholar
• 5 Sarkar G, Koeberl DD, Sommer SS. Direct sequencing of the activation peptide and the catalytic domain of the factor IX gene in six species. Genomics 1990; 06: 133-143.
  CrossrefPubMedGoogle Scholar
• 6 Elder B, Lakich D, Gitschier J. Sequence of the murine factor VIII cDNA. Genomics 1993; 16: 374-379.
  CrossrefPubMedGoogle Scholar
• 7 Emeis JJ, Jirouskova M, Muchitsch EM. et al. A guide to murine coagulation factor structure, function, assays, and genetic alterations. J Thromb Haemost 2007; 05: 670-679.
  CrossrefPubMedGoogle Scholar
• 8 Matsuo O, Lijnen HR, Ueshima S. et al. A guide to murine fibrinolytic factor structure, function, assays, and genetic alterations. J Thromb Haemost 2007; 05: 680-689.
  CrossrefPubMedGoogle Scholar
• 9 Jirouskova M, Shet AS, Johnson GJ. A guide to murine platelet structure, function, assays, and genetic alterations. J Thromb Haemost 2007; 05: 661-669.
  CrossrefPubMedGoogle Scholar
• 10 Walter J, High KA. Gene therapy for the hemophilias. Adv Vet Med 1997; 40: 119-134.
  PubMedGoogle Scholar
• 11 Wang L, Zoppe M, Hackeng TM. et al. A factor IX-deficient mouse model for hemophilia B gene therapy. Proc Natl Acad Sci USA 1997; 94: 11563-11566.
  CrossrefPubMedGoogle Scholar
• 12 Lin HF, Maeda N, Smithies O. et al. A coagulation factor IX-deficient mouse model for human hemophilia B. Blood 1997; 90: 3962-3966.
  PubMedGoogle Scholar
• 13 Kundu RK, Sangiorgi F, Wu LY. et al. Targeted inactivation of the coagulation factor IX gene causes hemophilia B in mice. Blood 1998; 92: 168-174.
  PubMedGoogle Scholar
• 14 Detloff PJ, Lewis J, John SW. et al. Deletion and replacement of the mouse adult beta-globin genes by a “plug and socket” repeated targeting strategy. Mol Cell Biol 1994; 14: 6936-6943.
  CrossrefPubMedGoogle Scholar
• 15 Jin DY, Zhang TP, Gui T. et al. Creation of a mouse expressing defective human factor IX. Blood 2004; 104: 1733-1739.
  CrossrefPubMedGoogle Scholar
• 16 Greenwood R, Wang B, Midkiff K. et al. Identification of T-cell epitopes in clotting factor IX and lack of tolerance in inbred mice. J Thromb Haemost 2003; 01: 95-102.
  CrossrefPubMedGoogle Scholar
• 17 Cao O, Armstrong E, Schlachterman A. et al. Immunedeviation by mucosal antigen administration suppresses gene-transfer-induced inhibitor formation to factor IX. Blood 2006; 108: 480-486.
  CrossrefPubMedGoogle Scholar
• 18 Mackman N. Tissue-specific hemostasis in mice. Arterioscler Thromb Vasc Biol 2005; 25: 2273-2281.
  CrossrefPubMedGoogle Scholar
• 19 Bugge TH, Xiao Q, Kombrinck KW. et al. Fatal embryonic bleeding events in mice lacking tissue factor, the cell-associated initiator of blood coagulation. Proc Natl Acad Sci USA 1996; 93: 6258-6263.
  CrossrefPubMedGoogle Scholar
• 20 Rosen ED, Chan JC, Idusogie E. et al. Mice lacking factor VII develop normally but suffer fatal perinatal bleeding. Nature 1997; 390: 290-294.
  CrossrefPubMedGoogle Scholar
• 21 Sun WY, Witte DP, Degen JL. et al. Prothrombin deficiency results in embryonic and neonatal lethality in mice. Proc Natl Acad Sci USA 1998; 95: 7597-7602.
  CrossrefPubMedGoogle Scholar
• 22 Xue J, Wu Q, Westfield LA. et al. Incomplete embryonic lethality and fatal neonatal hemorrhage caused by prothrombin deficiency in mice. Proc Natl Acad Sci USA 1998; 95: 7603-7607.
  CrossrefPubMedGoogle Scholar
• 23 Cui J, O’Shea KS, Purkayastha A. et al. Fatal haemorrhage and incomplete block to embryogenesis in mice lacking coagulation factor V. Nature 1996; 384: 66-68.
  CrossrefPubMedGoogle Scholar
• 24 Dewerchin M, Liang Z, Moons L. et al. Blood coagulation factor X deficiency causes partial embryonic lethality and fatal neonatal bleeding in mice. Thromb Haemost 2000; 83: 185-190.
  Article in Thieme ConnectPubMedGoogle Scholar
• 25 Zhu A, Sun H, Raymond Jr. RM. et al. Fatal hemorrhage in mice lacking gamma-glutamyl carboxylase. Blood 2007; 109: 5270-5275.
  CrossrefPubMedGoogle Scholar
• 26 Fields PA, Arruda VR, Armstrong E. et al. Risk and prevention of anti-factor IX formation in AAV-mediated gene transfer in the context of a large deletion of F9. Mol Ther 2001; 04: 201-210.
  CrossrefPubMedGoogle Scholar
• 27 Sabatino DE, Armstrong E, Edmonson S. et al. Novel hemophilia B mouse models exhibiting a range of mutations in the Factor IX gene. Blood 2004; 104: 2767-2774.
  CrossrefPubMedGoogle Scholar
• 28 Yang C, Feng J, Song W. et al. A mouse model for nonsense mutation bypass therapy shows a dramatic multiday response to geneticin. Proc Natl Acad Sci USA 2007; 104: 15394-15399.
  CrossrefPubMedGoogle Scholar
• 29 Kurachi S, Deyashiki Y, Takeshita J. et al. Genetic mechanisms of age regulation of human blood coagulation factor IX. Science 1999; 285: 739-743.
  CrossrefPubMedGoogle Scholar
• 30 Inoue Y, Peters LL, Yim SH. et al. Role of hepatocyte nuclear factor 4alpha in control of blood coagulation factor gene expression. J Mol Med 2006; 84: 334-344.
  CrossrefPubMedGoogle Scholar
• 31 Davies N, Austen DE, Wilde MD. et al. Clotting factor IX levels in C/EBP alpha knockout mice. Br J Haematol 1997; 99: 578-579.
  CrossrefPubMedGoogle Scholar
• 32 Sweeney JD, Hoernig LA. Age-dependent effect on the level of factor IX. Am J Clin Pathol 1993; 99: 687-688.
  CrossrefPubMedGoogle Scholar
• 33 Boland EJ, Liu YC, Walter CA. et al. Age-specific regulation of clotting factor IX gene expression in normal and transgenic mice. Blood 1995; 86: 2198-2205.
  PubMedGoogle Scholar
• 34 Brady JN, Notley C, Cameron C. et al. Androgen effects on factor IX expression: invitro and in-vivo studies in mice. Br J Haematol 1998; 101: 273-279.
  CrossrefPubMedGoogle Scholar
• 35 Gui T, Lin HF, Jin DY. et al. Circulating and binding characteristics of wild-type factor IX and certain Gla domain mutants in vivo. Blood 2002; 100: 153-158.
  CrossrefPubMedGoogle Scholar
• 36 Begbie ME, Mamdani A, Gataiance S. et al. An important role for the activation peptide domain in controlling factor IX levels in the blood of haemophilia B mice. Thromb Haemost 2005; 94: 1138-1147.
  Article in Thieme ConnectPubMedGoogle Scholar
• 37 Schuettrumpf J, Herzog RW, Schlachterman A. et al. Factor IX variants improve gene therapy efficacy for hemophilia B. Blood 2005; 105: 2316-2323.
  CrossrefPubMedGoogle Scholar
• 38 Dejana E, Callioni A, Quintana A. et al. Bleeding time in laboratory animals. II – A comparison of different assay conditions in rats. Thromb Res 1979; 15: 191-197.
  CrossrefPubMedGoogle Scholar
• 39 Broze Jr. GJ. Protein Z-dependent regulation of coagulation. Thromb Haemost 2001; 86: 8-13.
  Article in Thieme ConnectPubMedGoogle Scholar
• 40 Gailani D, Lasky NM, Broze Jr. GJ. A murine model of factor XI deficiency. Blood Coagul Fibrinolysis 1997; 08: 134-144.
  CrossrefPubMedGoogle Scholar
• 41 Tsakiris DA, Scudder L, Hodivala-Dilke K. et al. Hemostasis in the mouse (Mus musculus): a review. Thromb Haemost 1999; 81: 177-188.
  Article in Thieme ConnectPubMedGoogle Scholar
• 42 Broze Jr. GJ, Yin ZF, Lasky N. A tail vein bleeding time model and delayed bleeding in hemophiliac mice. Thromb Haemost 2001; 85: 747-748.
  Article in Thieme ConnectPubMedGoogle Scholar
• 43 Borchgrevink CF, Waaler BA. The secondary bleeding time. A new method for the differentiation of hemorrhagic diseases. Acta Med Scandinav 1958; 162: 361-374.
  PubMedGoogle Scholar
• 44 Tomokiyo K, Nakatomi Y, Araki T. et al. A novel therapeutic approach combining human plasma-derived Factors VIIa and X for haemophiliacs with inhibitors: evidence of a higher thrombin generation rate in vitro and more sustained haemostatic activity in vivo than obtained with Factor VIIa alone. Vox Sang 2003; 85: 290-299.
  CrossrefPubMedGoogle Scholar
• 45 Hoffman M, Harger A, Lenkowski A, Hedner U, Roberts HR, Monroe DM. Cutaneous wound healing is impaired in hemophilia B. Blood 2006; 108: 3053-3060.
  CrossrefPubMedGoogle Scholar
• 46 McDonald A, Hoffman M, Hedner U. et al. Restoring hemostatic thrombin generation at the time of cutaneous wounding does not normalize healing in hemophilia B. J Thromb Haemost 2007; 05: 1577-1583.
  CrossrefPubMedGoogle Scholar
• 47 McDonald AG, Yang K, Roberts HR. et al. Perivascular tissue factor is downregulated following cutaneous wounding: implications for bleeding in hemophilia. Blood 2008; 111: 2046-2048.
  CrossrefPubMedGoogle Scholar
• 48 Mejia-Carvajal C, Hakobyan N, Enockson C. et al. The impact of joint bleeding and synovitis on physical ability and joint function in a murine model of haemophilic synovitis. Haemophilia 2008; 14: 119-126.
  PubMedGoogle Scholar
• 49 Valentino LA, Hakobyan N. Histological changes in murine haemophilic synovitis: a quantitative grading system to assess blood-induced synovitis. Haemophilia 2006; 12: 654-662.
  CrossrefPubMedGoogle Scholar
• 50 Hakobyan N, Kazarian T, Valentino LA. Synovitis in a murine model of human factor VIII deficiency. Haemophilia 2005; 11: 227-232.
  CrossrefPubMedGoogle Scholar
• 51 Valentino LA, Hakobyan N, Kazarian T. et al. Experimental haemophilic synovitis: rationale and development of a murine model of human factor VIII deficiency. Haemophilia 2004; 10: 280-287.
  CrossrefPubMedGoogle Scholar
• 52 Sun J, Hakobyan N, Valentino LA. et al. Intra-articular factor IX protein or gene replacement protects against development of hemophilic synovitis in the abscence of circulating factor IX. Blood. 2008 epub ahead of print.
  PubMedGoogle Scholar
• 53 Wang X, Cheng Q, Xu L. et al. Effects of factor IX or factor XI deficiency on ferric chloride-induced carotid artery occlusion in mice. J Thromb Haemost 2005; 03: 695-702.
  CrossrefPubMedGoogle Scholar
• 54 Gui T, Reheman A, Funkhouser WK. et al. In vivo response to vascular injury in the absence of factor IX: examination in factor IX knockout mice. Thromb Res 2007; 121: 225-234.
  CrossrefPubMedGoogle Scholar
• 55 Renne T, Pozgajova M, Gruner S. et al. Defective thrombus formation in mice lacking coagulation factor XII. J Exp Med 2005; 202: 271-281.
  CrossrefPubMedGoogle Scholar
• 56 Gui T, Reheman A, Funkhouser WK. et al. In vivo response to vascular injury in the absence of factor IX: examination in FIX knockout mice. Thromb Res 2007; 121: 225-234.
  CrossrefPubMedGoogle Scholar
• 57 Gailani D, Renne T. Intrinsic pathway of coagulation and arterial thrombosis. Arterioscler Thromb Vasc Biol 2007; 27: 2507-2513.
  CrossrefPubMedGoogle Scholar
• 58 Cheng Q, Zhao Y, Lawson WE. et al. The effects of intrinsic pathway protease deficiencies on plasminogen-deficient mice. Blood 2005; 106: 3055-3057.
  CrossrefPubMedGoogle Scholar
• 59 van Hylckama Vlieg A, van der Linden IK, Bertina RM. et al. High levels of factor IX increase the risk of venous thrombosis. Blood 2000; 95: 3678-3682.
  PubMedGoogle Scholar
• 60 Lowe GD. Factor IX and thrombosis. Br J Haematol 2001; 115: 507-513.
  CrossrefPubMedGoogle Scholar
• 61 Woodward M, Lowe GD, Rumley A. et al. Epidemiology of coagulation factors, inhibitors and activation markers: The Third Glasgow MONICA Survey. II. Relationships to cardiovascular risk factors and prevalent cardiovascular disease. Br J Haematol 1997; 97: 785-797.
  CrossrefPubMedGoogle Scholar
• 62 Ameri A, Kurachi S, Sueishi K. et al. Myocardial fibrosis in mice with overexpression of human blood coagulation factor IX. Blood 2003; 101: 1871-1873.
  CrossrefPubMedGoogle Scholar
• 63 Shetty S, Ghosh K, Quadros L. Amelioration of clinical severity of similar mutations severe factor IX deficiency by coinherited thrombophilia. Eur J Haematol 2008; 80: 87-89.
  PubMedGoogle Scholar
• 64 Arbini AA, Mannucci PM, Bauer KA. Low prevalence of the factor V Leiden mutation among “severe” hemophiliacs with a “milder” bleeding diathesis. Thromb Haemost 1995; 74: 1255-1258.
  Article in Thieme ConnectPubMedGoogle Scholar
• 65 Schlachterman A, Schuettrumpf J, Liu JH. et al. Factor V Leiden improves in vivo hemostasis in murine hemophilia models. J Thromb Haemost 2005; 03: 2730-2737.
  CrossrefPubMedGoogle Scholar
• 66 White G, Roberts H. New Approaches for the therapy of bleeding disorders, including gene therapy. In: Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 5th Edition ed. Lippincott, Williams, and Wilkins; 2005
  Google Scholar
• 67 High KA. Update on progress and hurdles in novel genetic therapies for hemophilia. Hematology Am Soc Hematol Educ Program 2007; 2007: 466-472.
  CrossrefPubMedGoogle Scholar
• 68 Pierce GF, Lillicrap D, Pipe SW. et al. Gene therapy, bioengineered clotting factors and novel technologies for hemophilia treatment. J Thromb Haemost 2007; 05: 901-906.
  CrossrefPubMedGoogle Scholar
• 69 Chuah M, Vandendriessche T. Gene therapy for hemophilia “A” and “B”: efficacy, safety and immune consequences. Verh K Acad Geneeskd Belg 2007; 69: 315-334.
  PubMedGoogle Scholar
• 70 Miao CH. A novel gene expression system: non-viral gene transfer for hemophilia as model systems. Adv Genet 2005; 54: 143-177.
  PubMedGoogle Scholar
• 71 White SJ, Page SM, Margaritis P. et al. Long-term expression of human clotting factor IX from retrovirally transduced primary human keratinocytes in vivo. Hum Gene Ther 1998; 09: 1187-1195.
  CrossrefPubMedGoogle Scholar
• 72 Fair JH, Cairns BA, Lapaglia MA. et al. Correction of factor IX deficiency in mice by embryonic stem cells differentiated in vitro. Proc Natl Acad Sci USA 2005; 102: 2958-2963.
  CrossrefPubMedGoogle Scholar
• 73 Tatsumi K, Ohashi K, Kataoka M. et al. Successful in vivo propagation of factor IX-producing hepatocytes in mice: potential for cell-based therapy in haemophilia B. Thromb Haemost 2008; 99: 883-891.
  Article in Thieme ConnectPubMedGoogle Scholar
• 74 Bigger BW, Siapati EK, Mistry A. et al. Permanent partial phenotypic correction and tolerance in a mouse model of hemophilia B by stem cell gene delivery of human factor IX. Gene Ther 2006; 13: 117-126.
  CrossrefPubMedGoogle Scholar
• 75 Chang AH, Stephan MT, Sadelain M. Stem cell-derived erythroid cells mediate long-term systemic protein delivery. Nat Biotechnol 2006; 24: 1017-1021.
  CrossrefPubMedGoogle Scholar
• 76 Zhang G, Shi Q, Fahs SA. et al. Ectopic expression of human FIX in mouse platelets can store releasable FIX in platelets and may be a potential strategy for gene therapy of hemophilia B. Blood 2007; 110: 65a-66a.
  PubMedGoogle Scholar
• 77 Van Raamsdonk JM, Ross CJ, Potter MA. et al. Treatment of hemophilia B in mice with nonautologous somatic gene therapeutics. J Lab Clin Med 2002; 139: 35-42.
  CrossrefPubMedGoogle Scholar
• 78 Wen J, Vargas AG, Ofosu FA. et al. Sustained and therapeutic levels of human factor IX in hemophilia B mice implanted with microcapsules: key role of encapsulated cells. J Gene Med 2006; 08: 362-369.
  CrossrefPubMedGoogle Scholar
• 79 Wen J, Xu N, Li A. et al. Encapsulated human primary myoblasts deliver functional hFIX in hemophilic mice. J Gene Med 2007; 09: 1002-1010.
  CrossrefPubMedGoogle Scholar
• 80 Miao CH, Thompson AR, Loeb K. et al. Long-term and therapeutic-level hepatic gene expression of human factor IX after naked plasmid transfer in vivo. Mol Ther 2001; 03: 947-957.
  CrossrefPubMedGoogle Scholar
• 81 Miao CH, Brayman AA, Loeb KR. et al. Ultrasound enhances gene delivery of human factor IX plasmid. Hum Gene Ther 2005; 16: 893-905.
  CrossrefPubMedGoogle Scholar
• 82 Ye X, Loeb KR, Stafford DW. et al. Complete and sustained phenotypic correction of hemophilia B in mice following hepatic gene transfer of a high-expressing human factor IX plasmid. J Thromb Haemost 2003; 01: 103-111.
  CrossrefPubMedGoogle Scholar
• 83 Mikkelsen JG, Yant SR, Meuse L. et al. Helper-Independent Sleeping Beauty transposon-transposase vectors for efficient nonviral gene delivery and persistent gene expression in vivo. Mol Ther 2003; 08: 654-665.
  CrossrefPubMedGoogle Scholar
• 84 Liu F, Sag D, Wang J. et al. Sine-wave current for efficient and safe in vivo gene transfer. Mol Ther 2007; 15: 1842-1847.
  CrossrefPubMedGoogle Scholar
• 85 Keravala A, Chavez CL, Woodard LE. et al. Hemophilia gene therapy with PhiC31 integrase: A novel approach. Mol Ther. 2008 16. Abstract 877.
  PubMedGoogle Scholar
• 86 Jacobs F, Snoeys J, Feng Y. et al. Direct comparison of hepatocyte-specific expression cassettes following adenoviral and nonviral hydrodynamic gene transfer. Gene Ther 2008; 15: 594-603.
  CrossrefPubMedGoogle Scholar
• 87 Olivares EC, Hollis RP, Chalberg TW. et al. Site-specific genomic integration produces therapeutic factor IX levels in mice. Nat Biotechnol 2002; 20: 1124-1128.
  CrossrefPubMedGoogle Scholar
• 88 Kay MA, Rothenberg S, Landen CN. et al. In vivo gene therapy of hemophilia B: sustained partial correction in factor IX-deficient dogs. Science 1993; 262: 117-119.
  CrossrefPubMedGoogle Scholar
• 89 Fang B, Wang H, Gordon G. et al. Lack of persistence of E1– recombinant adenoviral vectors containing a temperature-sensitive E2A mutation in immunocompetent mice and hemophilia B dogs. Gene Ther 1996; 03: 217-222.
  PubMedGoogle Scholar
• 90 Yao SN, Farjo A, Roessler BJ. et al. Adenovirus-mediated transfer of human factor IX gene in immuno-deficient and normal mice: evidence for prolonged stability and activity of the transgene in liver. Viral Immunol 1996; 09: 141-153.
  CrossrefPubMedGoogle Scholar
• 91 Ehrhardt A, Kay MA. A new adenoviral helper-dependent vector results in long-term therapeutic levels of human coagulation factor IX at low doses in vivo. Blood 2002; 99: 3923-3930.
  CrossrefPubMedGoogle Scholar
• 92 Zhang J, Xu L, Haskins ME. et al. Neonatal gene transfer with a retroviral vector results in tolerance to human factor IX in mice and dogs. Blood 2004; 103: 143-151.
  CrossrefPubMedGoogle Scholar
• 93 Xu L, Mei M, Haskins ME. et al. Immune response after neonatal transfer of a human factor IX-expressing retroviral vector in dogs, cats, and mice. Thromb Res 2007; 120: 269-280.
  CrossrefPubMedGoogle Scholar
• 94 Brunetti-Pierri N, Palmer DJ, Mane V. et al. Increased hepatic transduction with reduced systemic dissemination and proinflammatory cytokines following hydrodynamic injection of helper-dependent adenoviral vectors. Mol Ther 2005; 12: 99-106.
  CrossrefPubMedGoogle Scholar
• 95 Dobrzynski E, Fitzgerald JC, Cao O. et al. Prevention of cytotoxic T lymphocyte responses to factor IX-expressing hepatocytes by gene transfer-induced regulatory T cells. Proc Natl Acad Sci USA 2006; 103: 4592-4597.
  CrossrefPubMedGoogle Scholar
• 96 McCaffrey AP, Fawcett P, Nakai H. et al. The host response to adenovirus, helper-dependent adenovirus, and adeno-associated virus in mouse liver. Mol Ther 2008; 16: 931-941.
  CrossrefPubMedGoogle Scholar
• 97 Brown BD, Cantore A, Annoni A. et al. A microRNA-regulated lentiviral vector mediates stable correction of hemophilia B mice. Blood 2007; 110: 4144-4152.
  CrossrefPubMedGoogle Scholar
• 98 Vandendriessche T, Thorrez L, Acosta-Sanchez A. et al. Efficacy and safety of adeno-associated viral vectors based on serotype 8 and 9 vs. lentiviral vectors for hemophilia B gene therapy. J Thromb Haemost 2007; 05: 16-24.
  CrossrefPubMedGoogle Scholar
• 99 Brown BD, Gentner B, Cantore A. et al. Endogenous microRNA can be broadly exploited to regulate transgene expression according to tissue, lineage and differentiation state. Nat Biotechnol 2007; 25: 1457-1467.
  CrossrefPubMedGoogle Scholar
• 100 Herzog RW, Hagstrom JN, Kung SH. et al. Stable gene transfer and expression of human blood coagulation factor IX after intramuscular injection of recombinant adeno-associated virus. Proc Natl Acad Sci USA 1997; 94: 5804-5809.
  CrossrefPubMedGoogle Scholar
• 101 Snyder RO, Miao C, Meuse L. et al. Correction of hemophilia B in canine and murine models using recombinant adeno-associated viral vectors. Nat Med 1999; 05: 64-70.
  CrossrefPubMedGoogle Scholar
• 102 Wang L, Takabe K, Bidlingmaier SM. et al. Sustained correction of bleeding disorder in hemophilia B mice by gene therapy. Proc Natl Acad Sci USA 1999; 96: 3906-3910.
  CrossrefPubMedGoogle Scholar
• 103 Wu Z, Sun J, Zhang T. et al. Optimization of self-complementary AAV vectors for liver-directed expression results in sustained correction of hemophilia B at low vector dose. Mol Ther 2008; 16: 280-289.
  CrossrefPubMedGoogle Scholar
• 104 Peng J, Wang H, Ma Y. et al. Non-invasive viral gene transfer of factor IX to colonic epithelial cells in haemophilia B mice. J Thromb Haemost 2008; 06: 1033-1035.
  CrossrefPubMedGoogle Scholar
• 105 Grimm D, Zhou S, Nakai H. et al. Preclinical in vivo evaluation of pseudotyped adeno-associated virus vectors for liver gene therapy. Blood 2003; 102: 2412-2419.
  CrossrefPubMedGoogle Scholar
• 106 Chao H, Monahan PE, Liu Y. et al. Sustained and complete phenotype correction of hemophilia B mice following intramuscular injection of AAV1 serotype vectors. Mol Ther 2001; 04: 217-222.
  CrossrefPubMedGoogle Scholar
• 107 Mingozzi F, Schuttrumpf J, Arruda VR. et al. Improved hepatic gene transfer by using an adeno-associated virus serotype 5 vector. J Virol 2002; 76: 10497-10502.
  CrossrefPubMedGoogle Scholar
• 108 Zhang TP, Jin DY, Wardrop 3rd RM. et al. Transgene expression levels and kinetics determine risk of humoral immune response modeled in factor IX knockout and missense mutant mice. Gene Ther 2007; 14: 429-440.
  CrossrefPubMedGoogle Scholar
• 109 Cohn EF, Zhuo J, Kelly ME. et al. Efficient induction of immune tolerance to coagulation factor IX following direct intramuscular gene transfer. J Thromb Haemost 2007; 05: 1227-1236.
  CrossrefPubMedGoogle Scholar
• 110 Arruda VR, Schuettrumpf J, Herzog RW. et al. Safety and efficacy of factor IX gene transfer to skeletal muscle in murine and canine hemophilia B models by adeno-associated viral vector serotype 1. Blood 2004; 103: 85-92.
  CrossrefPubMedGoogle Scholar
• 111 Monahan PE, Sun J, Valentino LA. et al. Adeno-associated Virus (AAV) mediated intraarticular expression of clotting factor IX protects from hemophilic arthropathy. Haemophilia 2008; 14: 407.
  PubMedGoogle Scholar
• 112 Nathwani AC, Gray JT, Ng CY. et al. Self-complementary adeno-associated virus vectors containing a novel liver-specific human factor IX expression cassette enable highly efficient transduction of murine and nonhuman primate liver. Blood 2006; 107: 2653-2661.
  CrossrefPubMedGoogle Scholar
• 113 Wu Z, Duan H, Samulski RJ. Self-complementary AAV2 vectors transduce liver with the same efficiency as AAV8: the critical role of second-strand synthesis in AAV biology. Mol Ther 2005; 11 (Suppl. 01) 5.
  PubMedGoogle Scholar
• 114 Stilwell JL, Samulski RJ. Role of viral vectors and virion shells in cellular gene expression. Mol Ther 2004; 09: 337-346.
  PubMedGoogle Scholar
• 115 Li C, Hirsch M, Asokan A. et al. Adeno-associated virus type 2 (AAV2) capsid-specific cytotoxic T lymphocytes eliminate only vector-transduced cells coexpressing the AAV2 capsid in vivo. J Virol 2007; 81: 7540-7547.
  CrossrefPubMedGoogle Scholar
• 116 Qiu X, Lu D, Zhou J. et al. Implantation of autologous skin fibroblast genetically modified to secrete clotting factor IX partially corrects the hemorrhagic tendencies in two hemophilia B patients. Chin Med J (Engl) 1996; 109: 832-839.
  PubMedGoogle Scholar
• 117 Manno CS, Chew AJ, Hutchison S. et al. AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood 2003; 101: 2963-2972.
  CrossrefPubMedGoogle Scholar
• 118 Manno CS, Pierce GF, Arruda VR. et al. Successful transduction of liver in hemophilia by AAV- Factor IX and limitations imposed by the host immune response. Nat Med 2006; 12: 342-347.
  CrossrefPubMedGoogle Scholar
• 119 Arruda VR, Hagstrom JN, Deitch J. et al. Posttranslational modifications of recombinant myotube-synthesized human factor IX. Blood 2001; 97: 130-138.
  CrossrefPubMedGoogle Scholar
• 120 Zhang TP, Jin DY, Wardrop 3rd RM. et al. Transgene expression levels and kinetics determine risk of humoral immune response modeled in factor IX knockout and missense mutant mice. Gene Ther 2007; 14: 429-440.
  CrossrefPubMedGoogle Scholar
• 121 Cheung WF, van den Born J, Kuhn K. et al. Identification of the endothelial cell binding site for factor IX. Proc Natl Acad Sci USA 1996; 93: 11068-11073.
  CrossrefPubMedGoogle Scholar
• 122 Wolberg AS, Stafford DW, Erie DA. Human factor IX binds to specific sites on the collagenous domain of collagen IV. J Biol Chem 1997; 272: 16717-16720.
  CrossrefPubMedGoogle Scholar
• 123 Recombinant DNA and Gene Transfer Meeting, Advances in Clinical Gene Therapy. June 19, 2007. Available at http://www4.od.nih.gov/oba/RAC/meeting.html NHGRI; 2007 Last accessed August 12, 2008.
  PubMed
• 124 DiMichele D. Inhibitor development in haemophilia B: an orphan disease in need of attention. Br J Haematol 2007; 138: 305-315.
  CrossrefPubMedGoogle Scholar
• 125 Thorland EC, Drost JB, Lusher JM. et al. Anaphylactic response to factor IX replacement therapy in haemophilia B patients: complete gene deletions confer the highest risk. Haemophilia 1999; 05: 101-105.
  CrossrefPubMedGoogle Scholar
• 126 Pike IM, Yount WJ, Puritz EM. et al. Immunochemical characterization of a monoclonal G4, lambda human antibody to factor IX. Blood 1972; 40: 1-10.
  PubMedGoogle Scholar
• 127 Sawamoto Y, Shima M, Yamamoto M. et al. Measurement of anti-factor IX IgG subclasses in haemophilia B patients who developed inhibitors with episodes of allergic reactions to factor IX concentrates. Thromb Res 1996; 83: 279-286.
  CrossrefPubMedGoogle Scholar
• 128 Dioun AF, Ewenstein BM, Geha RS. et al. IgE-mediated allergy and desensitization to factor IX in hemophilia B. J Allergy Clin Immunol 1998; 102: 113-117.
  CrossrefPubMedGoogle Scholar
• 129 Christophe OD, Lenting PJ, Cherel G. et al. Functional mapping of anti-factor IX inhibitors developed in patients with severe hemophilia B. Blood 2001; 98: 1416-1423.
  CrossrefPubMedGoogle Scholar
• 130 Tengborn L, Hansson S, Fasth A. et al. Anaphylactoid reactions and nephrotic syndrome--a considerable risk during factor IX treatment in patients with haemophilia B and inhibitors: a report on the outcome in two brothers. Haemophilia 1998; 04: 854-859.
  CrossrefPubMedGoogle Scholar
• 131 Lozier JN, Tayebi N, Zhang P. Mapping of genes that control the antibody response to human factor IX in mice. Blood 2005; 105: 1029-1035.
  PubMedGoogle Scholar
• 132 Fields PA, Kowalczyk DW, Arruda VR. et al. Role of vector in activation of T cell subsets in immune responses against the secreted transgene product factor IX. Mol Ther 2000; 01: 225-235.
  CrossrefPubMedGoogle Scholar
• 133 Chen J, Wu Q, Yang P. et al. Determination of specific CD4 and CD8 T cell epitopes after AAV2– and AAV8-hF.IX gene therapy. Mol Ther 2006; 13: 260-269.
  CrossrefPubMedGoogle Scholar
• 134 Hay CR, Ollier W, Pepper L. et al. HLA class II profile: a weak determinant of factor VIII inhibitor development in severe haemophilia A. UKHCDO Inhibitor Working Party. Thromb Haemost 1997; 77: 234-237.
  Article in Thieme ConnectPubMedGoogle Scholar
• 135 Oldenburg J, Picard JK, Schwaab R. et al. HLA genotype of patients with severe haemophilia A due to intron 22 inversion with and without inhibitors of factor VIII. Thromb Haemost 1997; 77: 238-242.
  Article in Thieme ConnectPubMedGoogle Scholar
• 136 Astermark J, Oldenburg J, Pavlova A. et al. Polymorphisms in the IL10 but not in the IL1beta and IL4 genes are associated with inhibitor development in patients with hemophilia A. Blood 2006; 107: 3167-3172.
  CrossrefPubMedGoogle Scholar
• 137 Astermark J, Oldenburg J, Carlson J. et al. Polymorphisms in the TNFA gene and the risk of inhibitor development in patients with hemophilia A. Blood 2006; 108: 3739-3745.
  CrossrefPubMedGoogle Scholar
• 138 Astermark J, Wang X, Oldenburg J. et al. Polymorphisms in the CTLA-4 gene and inhibitor development in patients with severe hemophilia A. J Thromb Haemost 2007; 05: 263-265.
  CrossrefPubMedGoogle Scholar
• 139 Zhang HG, High KA, Wu Q. et al. Genetic analysis of the antibody response to AAV2 and factor IX. Mol Ther 2005; 11: 866-874.
  CrossrefPubMedGoogle Scholar
• 140 Mingozzi F, Liu YL, Dobrzynski E. et al. Induction of immune tolerance to coagulation factor IX antigen by in vivo hepatic gene transfer. J Clin Invest 2003; 111: 1347-1356.
  CrossrefPubMedGoogle Scholar
• 141 Cao O, Dobrzynski E, Wang L. et al. Induction and role of regulatory CD4+CD25+ T cells in tolerance to the transgene product following hepatic in vivo gene transfer. Blood 2007; 110: 1132-1140.
  CrossrefPubMedGoogle Scholar
• 142 Reding MT. Immunological aspects of inhibitor development. Haemophilia 2006; 12 (Suppl. 06) 30-36.
  PubMedGoogle Scholar
• 143 Hu G, Guo D, Key NS. et al. Cytokine production by CD4+ T cells specific for coagulation factor VIII in healthy subjects and haemophilia A patients. Thromb Haemost 2007; 97: 788-794.
  Article in Thieme ConnectPubMedGoogle Scholar
• 144 Monahan PE. Neonatal immune tolerance for hemophilia: can we “tolerate” new paradigms for gene therapy trials?. J Thromb Haemost 2007; 05: 1801-1804.
  CrossrefPubMedGoogle Scholar
• 145 Xu L, Gao C, Sands MS. et al. Neonatal or hepatocyte growth factor-potentiated adult gene therapy with a retroviral vector results in therapeutic levels of canine factor IX for hemophilia B. Blood 2003; 101: 3924-3932.
  CrossrefPubMedGoogle Scholar
• 146 Schneider H, Muhle C, Douar AM. et al. Sustained delivery of therapeutic concentrations of human clotting factor IX--a comparison of adenoviral and AAV vectors administered in utero. J Gene Med 2002; 04: 46-53.
  CrossrefPubMedGoogle Scholar
• 147 Waddington SN, Nivsarkar MS, Mistry AR. et al. Permanent phenotypic correction of hemophilia B in immunocompetent mice by prenatal gene therapy. Blood 2004; 104: 2714-2721.
  CrossrefPubMedGoogle Scholar
• 148 Sabatino DE, Mackenzie TC, Peranteau W. et al. Persistent expression of hF.IX After tolerance induction by in utero or neonatal administration of AAV-1-F.IX in hemophilia B mice. Mol Ther 2007; 15: 1677-1685.
  CrossrefPubMedGoogle Scholar
• 149 Xu L, Nichols TC, Sarkar R. et al. Absence of a desmopressin response after therapeutic expression of factor VIII in hemophilia A dogs with liver-directed neonatal gene therapy. Proc Natl Acad Sci USA 2005; 102: 6080-6085.
  CrossrefPubMedGoogle Scholar
• 150 Santagostino E, Mancuso ME, Rocino A. et al. Environmental risk factors for inhibitor development in children with haemophilia A: a case-control study. Br J Haematol 2005; 130: 422-427.
  CrossrefPubMedGoogle Scholar
• 151 Gouw SC, van den Berg HM, le Cessie S. et al. Treatment characteristics and the risk of inhibitor development: a multicenter cohort study among previously untreated patients with severe hemophilia A. J Thromb Haemost 2007; 05: 1383-1390.
  CrossrefPubMedGoogle Scholar
• 152 Chang J, Jin J, Lollar P. et al. Changing residue 338 in human factor IX from arginine to alanine causes an increase in catalytic activity. J Biol Chem 1998; 273: 12089-12094.
  CrossrefPubMedGoogle Scholar
• 153 Brunetti-Pierri N, Grove N, Zuo Y. et al. Bioengineered factor IX molecules with increased catalytic activity improve the safety and efficacy of helper-dependent adenoviral vectors (HDAd) for hemophilia B gene therapy. Mol Ther 2008; 16 (Suppl. 01) S152.
  PubMedGoogle Scholar
• 154 Refino CJ, Jeet S, DeGuzman L. et al. A human antibody that inhibits factor IX/IXa function potently inhibits arterial thrombosis without increasing bleeding. Arterioscler Thromb Vasc Biol 2002; 22: 517-522.
  CrossrefPubMedGoogle Scholar
• 155 Gruber A, Hanson SR. Factor XI-dependence of surface- and tissue factor-initiated thrombus propagation in primates. Blood 2003; 102: 953-955.
  CrossrefPubMedGoogle Scholar
• 156 Reipert BM, Hausl C, Sasgary M. et al. Humanized E17 hemophilic mice are a major breakthrough in teh design of new preclinical models for devoping factor VIII products with reduced immunogenicity. Blood. 2007 110. Abstract #782.
  PubMedGoogle Scholar
• 157 Jiang Q, Zhang L, Wang R. et al. FoxP3+CD4+ Treg cells play an important role in acute HIV-1 infection in humanized rag2-/-γC-/- mice in vivo . Blood. 2008 June; epub ahead of print.
  PubMedGoogle Scholar
• 158 Monahan PE. Experimental animal use in the study of haemophilic bleeding. Haemophilia 2008; 14: 112-116.
  PubMedGoogle Scholar
• 159 Yan JB, Wang S, Huang WY. et al. Transgenic mice can express mutant human coagulation factor IX with higher level of clotting activity. Biochem Genet 2006; 44: 349-360.
  PubMedGoogle Scholar