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General Review Article

Hemophilia Gene Therapy: New Development from Bench to Bed Side

Author(s): Xiao-Lu Guo, Tsai-Hua Chung, Yue Qin, Jie Zheng, Huyong Zheng, Liyuan Sheng, Tung Wynn and Lung-Ji Chang*

Volume 19, Issue 4, 2019

Page: [264 - 273] Pages: 10

DOI: 10.2174/1566523219666190924121836

Abstract

Novel gene therapy strategies have changed the prognosis of many inherited diseases in recent years. New development in genetic tools and study models has brought us closer to a complete cure for hemophilia. This review will address the latest gene therapy research in hemophilia A and B including gene therapy tools, genetic strategies and animal models. It also summarizes the results of recent clinical trials. Potential solutions are discussed regarding the current barriers in gene therapy for hemophilia.

Keywords: Gene therapy, lentiviral vector, hemophilia, recessive disorder, novel gene therapy, hemostasis.

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[1]
Nathwani AC, Davidoff AM, Tuddenham EGD. Advances in gene therapy for hemophilia. Hum Gene Ther 2017; 28(11): 1004-12.
[http://dx.doi.org/10.1089/hum.2017.167] [PMID: 28835123]
[2]
Nathwani AC, Tuddenham EGD. Epidemiology of coagulation disorders. Baillieres Clin Haematol 1992; 5(2): 383-439.
[http://dx.doi.org/10.1016/S0950-3536(11)80025-9] [PMID: 1511181]
[3]
Saldanha J, Minor P. Detection of human parvovirus B19 DNA in plasma pools and blood products derived from these pools: Implications for efficiency and consistency of removal of B19 DNA during manufacture. Br J Haematol 1996; 93(3): 714-9.
[http://dx.doi.org/10.1046/j.1365-2141.1996.d01-1679.x] [PMID: 8652400]
[4]
Pipe SW. The hope and reality of long-acting hemophilia products. Am J Hematol 2012; 87(S1): S33-9.
[http://dx.doi.org/10.1002/ajh.23146] [PMID: 22389200]
[5]
Kitchen S, Tiefenbacher S, Gosselin R. Factor activity assays for monitoring extended half-life FVIII and factor IX replacement therapies. Semin Thromb Hemost 2017; 43(3): 331-7.
[http://dx.doi.org/10.1055/s-0037-1598058] [PMID: 28264199]
[6]
Rogers GL, Herzog RW. Gene therapy for hemophilia. Front Biosci 2015; 20(8): 556-603.
[PMID: 25553466]
[7]
Herzog RW, Cao O, Srivastava A. Two decades of clinical gene therapy--success is finally mounting. Discov Med 2010; 9(45): 105-11.
[PMID: 20193635]
[8]
Castaldo G, Nardiello P, Bellitti F, et al. Haemophilia B: From molecular diagnosis to gene therapy. Clin Chem Lab Med 2003; 41(4): 445-51.
[http://dx.doi.org/10.1515/CCLM.2003.067] [PMID: 12747585]
[9]
Fagiuoli S, Daina E, D’Antiga L, Colledan M, Remuzzi G. Monogenic diseases that can be cured by liver transplantation. J Hepatol 2013; 59(3): 595-612.
[http://dx.doi.org/10.1016/j.jhep.2013.04.004] [PMID: 23578885]
[10]
Vehar GA, Keyt B, Eaton D, et al. Structure of human factor VIII. Nature 1984; 312(5992): 337-42.
[http://dx.doi.org/10.1038/312337a0] [PMID: 6438527]
[11]
High KH, Nathwani A, Spencer T, Lillicrap D. Current status of haemophilia gene therapy. Haemophilia 2014; 20(4): 43-9.
[http://dx.doi.org/10.1111/hae.12411] [PMID: 24762274]
[12]
den Uijl IEM, Fischer K, Van Der Bom JG, Grobbee DE, Rosendaal FR, Plug I. Analysis of low frequency bleeding data: The association of joint bleeds according to baseline FVIII activity levels. Haemophilia 2011; 17(1): 41-4.
[http://dx.doi.org/10.1111/j.1365-2516.2010.02383.x] [PMID: 20825504]
[13]
Siner JI, Iacobelli NP, Sabatino DE, et al. Minimal modification in the factor VIII B-domain sequence ameliorates the murine hemophilia A phenotype. Blood 2013; 121(21): 4396-403.
[http://dx.doi.org/10.1182/blood-2012-10-464164] [PMID: 23372167]
[14]
Bi L, Lawler AM, Antonarakis SE, High KA, Gearhart JD, Kazazian HH Jr. Targeted disruption of the mouse factor VIII gene produces a model of haemophilia A. Nat Genet 1995; 10(1): 119-21.
[http://dx.doi.org/10.1038/ng0595-119] [PMID: 7647782]
[15]
Di MG, Cerbone AM, Coppola A, et al. Longer-acting factor VIII to overcome limitations in haemophilia management: The PEGylated liposomes formulation issue. Haemophilia 2010; 16(1): 2-6.
[16]
Lin HF, Maeda N, Smithies O, Straight DL, Stafford DW. A coagulation factor IX-deficient mouse model for human hemophilia B. Blood 1997; 90(10): 3962-6.
[PMID: 9354664]
[17]
Jin DY, Zhang TP, Gui T, Stafford DW, Monahan PE. Creation of a mouse expressing defective human factor IX. Blood 2004; 104(6): 1733-9.
[http://dx.doi.org/10.1182/blood-2004-01-0138] [PMID: 15178576]
[18]
Reipert BM, Steinitz KN, van Helden PM, et al. Opportunities and limitations of mouse models humanized for HLA class II antigens. J Thromb Haemost 2009; 7(1): 92-7.
[http://dx.doi.org/10.1111/j.1538-7836.2009.03403.x] [PMID: 19630777]
[19]
Yen CT, Fan MN, Yang YL, Chou SC, Yu IS, Lin SW. Current animal models of hemophilia: The state of the art. Thromb J 2016; 14(1): 22.
[http://dx.doi.org/10.1186/s12959-016-0106-0] [PMID: 27766048]
[20]
Booth CJ, Brooks MB, Rockwell S. Spontaneous coagulopathy in inbred WAG/RijYcb rats. Comp Med 2010; 60(1): 25-30.
[PMID: 20158945]
[21]
Graham JB, Buckwalter JA, et al. Canine hemophilia; observations on the course, the clotting anomaly, and the effect of blood transfusions. J Exp Med 1949; 90(2): 97-111.
[http://dx.doi.org/10.1084/jem.90.2.97] [PMID: 18136192]
[22]
Giles AR, Tinlin S, Greenwood R. A canine model of hemophilic (factor VIII: C deficiency) bleeding. Blood 1982; 60(3): 727-30.
[PMID: 6809076]
[23]
Sabatino DE, Lange AM, Altynova ES, et al. Efficacy and safety of long-term prophylaxis in severe hemophilia A dogs following liver gene therapy using AAV vectors. Mol Ther 2011; 19(3): 442-9.
[http://dx.doi.org/10.1038/mt.2010.240] [PMID: 21081906]
[24]
Herzog RW, Arruda VR, Fisher TH, Read MS, Nichols TC, High KA. Absence of circulating factor IX antigen in hemophilia B dogs of the UNC-Chapel Hill colony. Thromb Haemost 2000; 84(2): 352-4.
[http://dx.doi.org/10.1055/s-0037-1614021] [PMID: 10959714]
[25]
Mauser AE, Whitlark J, Whitney KM, Lothrop CD Jr. A deletion mutation causes hemophilia B in Lhasa Apso dogs. Blood 1996; 88(9): 3451-5.
[PMID: 8896410]
[26]
Brooks MB, Gu W, Ray K. Complete deletion of factor IX gene and inhibition of factor IX activity in a labrador retriever with hemophilia B. J Am Vet Med Assoc 1997; 211(11): 1418-21.
[PMID: 9394892]
[27]
Neuenschwander S, Kissling-Albrecht L, Heiniger J, Backfisch W, Stranzinger G, Pliska V. Inherited defect of blood clotting factor VIII (haemophilia A) in sheep. Thromb Haemost 1992; 68(5): 618-20.
[http://dx.doi.org/10.1055/s-0038-1646328] [PMID: 1455410]
[28]
Porada CD, Sanada C, Long CR, et al. Clinical and molecular characterization of a re-established line of sheep exhibiting hemophilia A. J Thromb Haemost 2010; 8(2): 276-85.
[http://dx.doi.org/10.1111/j.1538-7836.2009.03697.x] [PMID: 19943872]
[29]
Porada CD, Almeida-Porada G. Treatment of hemophilia A in utero and postnatally using sheep as a model for cell and gene delivery. J Genet Syndr Gene Ther 2012; S1: 011.
[PMID: 23264887]
[30]
Kashiwakura Y, Mimuro J, Onishi A, et al. Porcine model of hemophilia A. PLoS One 2012; 7(11)e49450
[http://dx.doi.org/10.1371/journal.pone.0049450] [PMID: 23209578]
[31]
Tomokiyo K, Teshima K, Nakatomi Y, et al. Induction of acquired factor IX inhibitors in cynomolgus monkey (Macaca fascicularis): A new primate model of hemophilia B. Thromb Res 2001; 102(4): 363-74.
[http://dx.doi.org/10.1016/S0049-3848(01)00253-5] [PMID: 11369429]
[32]
Kiachopoulos S, Heske J, Tatzelt J, Winklhofer KF. Misfolding of the prion protein at the plasma membrane induces endocytosis, intracellular retention and degradation. Traffic 2004; 5(6): 426-36.
[http://dx.doi.org/10.1111/j.1398-9219.2004.00185.x] [PMID: 15117317]
[33]
Pipe SW. The promise and challenges of bioengineered recombinant clotting factors. J Thromb Haemost 2005; 3(8): 1692-701.
[http://dx.doi.org/10.1111/j.1538-7836.2005.01367.x] [PMID: 16102035]
[34]
Steven W. The secretion efficiency of factor VIII can be regulated by the size and oligosaccharide content of the B domain. Blood 2005; 106: 687.
[35]
Suwanmanee T, Hu G, Gui T, et al. Integration-deficient lentiviral vectors expressing codon-optimized R338L human FIX restore normal hemostasis in Hemophilia B mice. Mol Ther 2014; 22(3): 567-74.
[http://dx.doi.org/10.1038/mt.2013.188] [PMID: 23941813]
[36]
Piganeau G, Mouchiroud D, Duret L, Gautier C. Expected relationship between the silent substitution rate and the GC content: Implications for the evolution of isochores. J Mol Evol 2002; 54(1): 129-33.
[http://dx.doi.org/10.1007/s00239-001-0011-3] [PMID: 11734906]
[37]
Navarrete A, Dasgupta S, Delignat S, et al. Splenic marginal zone antigen-presenting cells are critical for the primary allo-immune response to therapeutic factor VIII in hemophilia A. J Thromb Haemost 2009; 7(11): 1816-23.
[http://dx.doi.org/10.1111/j.1538-7836.2009.03571.x] [PMID: 19682235]
[38]
Cantore A, Ranzani M, Bartholomae CC, et al. Liver-directed lentiviral gene therapy in a dog model of hemophilia B. Sci Transl Med 2015; 7(277)277ra28
[http://dx.doi.org/10.1126/scitranslmed.aaa1405] [PMID: 25739762]
[39]
Greig JA, Wang Q, Reicherter AL, et al. Characterization of AAV-mediated human factor VIII gene therapy in hemophilia A mice. Hum Gene Ther 2017; 28(5): 392-402.
[http://dx.doi.org/10.1089/hum.2016.128] [PMID: 28056565]
[40]
Shahani T, Covens K, Lavend’homme R, et al. Human liver sinusoidal endothelial cells but not hepatocytes contain factor VIII. J Thromb Haemost 2014; 12(1): 36-42.
[http://dx.doi.org/10.1111/jth.12412] [PMID: 24118899]
[41]
Wang X, Terhorst C, Herzog RW. In vivo induction of regulatory T cells for immune tolerance in hemophilia. Cell Immunol 2016; 301: 18-29.
[http://dx.doi.org/10.1016/j.cellimm.2015.10.001] [PMID: 26454643]
[42]
Over J, Sixma JJ, Bruïne MH, et al. Survival of 125 iodine-labeled Factor VIII in normals and patients with classic hemophilia. Observations on the heterogeneity of human Factor VIII. J Clin Invest 1978; 62(2): 223-34.
[http://dx.doi.org/10.1172/JCI109120] [PMID: 670391]
[43]
Yarovoi HV, Kufrin D, Eslin DE, et al. Factor VIII ectopically expressed in platelets: Efficacy in hemophilia A treatment. Blood 2003; 102(12): 4006-13.
[http://dx.doi.org/10.1182/blood-2003-05-1519] [PMID: 12881300]
[44]
Shi Q, Fahs SA, Wilcox DA, Weiler H, Haberichter RL, Montgome RR. Endothelial and platelet FVIII/VWF expression - divergence in clinical effect in murine models of hemophilia A with and without FVIII inhibitory antibodies. Blood 2006; (108): 3286.
[45]
Baumgartner CK, Mattson JG, Weiler H, Shi Q, Montgomery RR. Targeting factor VIII expression to platelets for hemophilia A gene therapy does not induce an apparent thrombotic risk in mice. J Thromb Haemost 2017; 15(1): 98-109.
[http://dx.doi.org/10.1111/jth.13436] [PMID: 27496751]
[46]
Herzog RW, Hagstrom JN. Gene therapy for hereditary hematological disorders. Am J Pharmacogenomics 2001; 1(2): 137-44.
[http://dx.doi.org/10.2165/00129785-200101020-00006] [PMID: 12174674]
[47]
Liu YL, Mingozzi F, Rodriguéz-Colôn SM, et al. Therapeutic levels of factor IX expression using a muscle-specific promoter and adeno-associated virus serotype 1 vector. Hum Gene Ther 2004; 15(8): 783-92.
[http://dx.doi.org/10.1089/1043034041648453] [PMID: 15319035]
[48]
Herzog RW, Yang EY, Couto LB, et al. Long-term correction of canine hemophilia B by gene transfer of blood coagulation factor IX mediated by adeno-associated viral vector. Nat Med 1999; 5(1): 56-63.
[http://dx.doi.org/10.1038/4743] [PMID: 9883840]
[49]
VandenDriessche T, Vanslembrouck V, Goovaerts I, et al. Long-term expression of human coagulation factor VIII and correction of hemophilia A after in vivo retroviral gene transfer in factor VIII-deficient mice. Proc Natl Acad Sci USA 1999; 96(18): 10379-84.
[http://dx.doi.org/10.1073/pnas.96.18.10379] [PMID: 10468616]
[50]
Roehl HH, Leibbrandt ME, Greengard JS, et al. Analysis of testes and semen from rabbits treated by intravenous injection with a retroviral vector encoding the human factor VIII gene: No evidence of germ line transduction. 2000; 11(18): 2529-40.
[http://dx.doi.org/10.1089/10430340050208000]
[51]
Naldini L. Lentiviruses as gene transfer agents for delivery to non-dividing cells. Curr Opin Biotechnol 1998; 9(5): 457-63.
[http://dx.doi.org/10.1016/S0958-1669(98)80029-3] [PMID: 9821272]
[52]
Shi Q, Kuether EL, Chen Y, Schroeder JA, Fahs SA, Montgomery RR. Platelet gene therapy corrects the hemophilic phenotype in immunocompromised hemophilia A mice transplanted with genetically manipulated human cord blood stem cells. Blood 2014; 123(3): 395-403.
[http://dx.doi.org/10.1182/blood-2013-08-520478] [PMID: 24269957]
[53]
Ward P, Walsh CE. Current and future prospects for hemophilia gene therapy. Expert Rev Hematol 2016; 9(7): 649-59.
[http://dx.doi.org/10.1080/17474086.2016.1182859] [PMID: 27153210]
[54]
Ponder KP. Gene therapy for hemophilia. Curr Opin Hematol 2006; 13(5): 301-7.
[http://dx.doi.org/10.1097/01.moh.0000239700.94555.b1] [PMID: 16888433]
[55]
Boisgérault F, Mingozzi F. The skeletal muscle environment and its role in immunity and tolerance to AAV vector-mediated gene transfer. Curr Gene Ther 2015; 15(4): 381-94.
[http://dx.doi.org/10.2174/1566523215666150630121750] [PMID: 26122097]
[56]
Perrin GQ, Herzog RW, Markusic DM. Update on clinical gene therapy for hemophilia. Blood 2019; 133(5): 407-14.
[http://dx.doi.org/10.1182/blood-2018-07-820720] [PMID: 30559260]
[57]
Kaneda Y. Update on non-viral delivery methods for cancer therapy: Possibilities of a drug delivery system with anticancer activities beyond delivery as a new therapeutic tool. Expert Opin Drug Deliv 2010; 7(9): 1079-93.
[http://dx.doi.org/10.1517/17425247.2010.510511] [PMID: 20716020]
[58]
Gloeckner C. Modified transposases for improved insertion sequence bias and increased DNA input tolerance United States Patent Application 20180298356 2017.
[59]
Mikkelsen JG, Yant SR, Meuse L, Huang Z, Xu H, Kay MA. Helper-Independent Sleeping Beauty transposon-transposase vectors for efficient nonviral gene delivery and persistent gene expression in vivo. Mol Ther 2003; 8(4): 654-65.
[http://dx.doi.org/10.1016/S1525-0016(03)00216-8] [PMID: 14529839]
[60]
Bowman K, Sarkar R, Raut S, Leong KW. Gene trsnafer to hemophilia A mice via oral delivery of FVIII-chitosan nanoparticles 2008; 132(3): 252-9.
[61]
Liu L, Rice MC, Kmiec EB. In vivo gene repair of point and frameshift mutations directed by chimeric RNA/DNA oligonucleotides and modified single-stranded oligonucleotides. Nucleic Acids Res 2001; 29(20): 4238-50.
[http://dx.doi.org/10.1093/nar/29.20.4238] [PMID: 11600713]
[62]
Brendel C, Klahold E, Gärtner J, Huppke P. Suppression of nonsense mutations in Rett syndrome by aminoglycoside antibiotics. Pediatr Res 2009; 65(5): 520-3.
[http://dx.doi.org/10.1203/PDR.0b013e31819d9ebc] [PMID: 19190538]
[63]
Chao H, Mansfield SG, Bartel RC, et al. Phenotype correction of hemophilia A mice by spliceosome-mediated RNA trans-splicing. Nat Med 2003; 9(8): 1015-9.
[http://dx.doi.org/10.1038/nm900] [PMID: 12847523]
[64]
Kren BT, Unger GM, Sjeklocha L, et al. Nanocapsule-delivered Sleeping Beauty mediates therapeutic Factor VIII expression in liver sinusoidal endothelial cells of hemophilia A mice. J Clin Invest 2009; 119(7): 2086-99.
[http://dx.doi.org/10.1172/JCI34332] [PMID: 19509468]
[65]
Worsham DN, Schuesler T, von Kalle C, Pan D. In vivo gene transfer into adult stem cells in unconditioned mice by in situ delivery of a lentiviral vector. Mol Ther 2006; 14(4): 514-24.
[http://dx.doi.org/10.1016/j.ymthe.2006.05.014] [PMID: 16893684]
[66]
Wang X, Shin SC, Chiang AF, et al. Intraosseous delivery of lentiviral vectors targeting factor VIII expression in platelets corrects murine hemophilia A. Mol Ther 2015; 23(4): 617-26.
[http://dx.doi.org/10.1038/mt.2015.20] [PMID: 25655313]
[67]
Brackmann HH, Gormsen J. Massive factor-VIII infusion in haemophiliac with factor-VIII inhibitor, high responder. Lancet 1977; 2(8044): 933-3.
[http://dx.doi.org/10.1016/S0140-6736(77)90871-6] [PMID: 72276]
[68]
Brackmann HH, White NG, Berntorp E, Andersen T, Escuriolaettingshausen C. Immune tolerance induction: What have we learned over time? Haemophilia 2018; 24(Suppl. 3): 3.
[69]
Meeks SL, Batsuli G. Hemophilia and inhibitors: Current treatment options and potential new therapeutic approaches. Hematology (Am Soc Hematol Educ Program) 2016; 2016(1): 657-62.
[http://dx.doi.org/10.1182/asheducation-2016.1.657] [PMID: 27913543]
[70]
White GC II, Kempton CL, Grimsley A, Nielsen B, Roberts HR. Cellular immune responses in hemophilia: Why do inhibitors develop in some, but not all hemophiliacs? J Thromb Haemost 2005; 3(8): 1676-81.
[http://dx.doi.org/10.1111/j.1538-7836.2005.01375.x] [PMID: 16102033]
[71]
Chen Y, Luo X, Schroeder JA, et al. Immune tolerance induced by platelet-targeted factor VIII gene therapy in hemophilia A mice is CD4 T cell mediated. J Thromb Haemost 2017; 15(10): 1994-2004.
[http://dx.doi.org/10.1111/jth.13800] [PMID: 28799202]
[72]
Merlin S, Cannizzo ES, Borroni E, et al. A novel platform for immune tolerance induction in hemophilia A mice. Mol Ther 2017; 25(8): 1815-30.
[http://dx.doi.org/10.1016/j.ymthe.2017.04.029] [PMID: 28552407]
[73]
Nathwani AC, Reiss UM, Tuddenham EG, et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med 2014; 371(21): 1994-2004.
[http://dx.doi.org/10.1056/NEJMoa1407309] [PMID: 25409372]
[74]
Weber A, Engelmaier A, Voelkel D, et al. Development of methods for the selective measurement of the single amino acid exchange variant coagulation factor IX padua. Mol Ther Methods Clin Dev 2018; 10: 29-37.
[http://dx.doi.org/10.1016/j.omtm.2018.05.004] [PMID: 30003118]

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