Seminars in Hematology
Volume 41, Issue 4 , Pages 287-296 , October 2004

Gene therapy of the hemophilias

  • Jay Lozier

      Affiliations

    • Food and Drug Administration Center for Biologics Evaluation and Research, Rockville, MD USA
    • Corresponding Author InformationAddress correspondence to Jay Lozier, MD, PhD, Senior Staff Fellow, FDA Center for Biologics Evaluation and Research, 1401 Rockville Pike HFM 340, Rockville, MD 20852-1448

References 

  1. Lozier JN , Brinkhous KM . Gene therapy and the hemophilias . J Am Med Assoc . 1994;271:47–51
  2. Petrini P , Lindvall N , Egberg N , Blomback M . Prophylaxis with factor concentrates in preventing hemophilic arthropathy . Am J Pediatr Hematol Oncol . 1991;13:280–287
  3. Bi L , Lawler AM , Antonarakis SE , High KA , Gearhart JD , Kazazian HH . Targeted disruption of the mouse factor VIII gene produces a model of haemophilia A . Nat Genet . 1995;10:119–121
  4. Bi L , Sarkar R , Naas T , Lawler AM , Pain J , Shumaker SL , et al.   Further characterization of factor VIII-deficient mice created by gene targeting (RNA and protein studies) . Blood . 1996;88:3446–3450
  5. Lin H-F , Maeda N , Smithies O , Straight DL , Stafford DW . A coagulation factor IX-deficient mouse model for human hemophilia B . Blood . 1997;90:3962–3966
  6. Wang L , Zoppe M , Hackeng TM , Griffin JH , Lee K-F , Verma IM . A factor IX-deficient mouse model for hemophilia B gene therapy . Proc Natl Acad Sci USA . 1997;94:11563–11566
  7. Kundu RK , Sangiorgi F , Wu LY , Kurachi K , Anderson WF , Maxson R , et al.   Targeted inactivation of the coagulation factor IX gene causes hemophilia B in mice . Blood . 1998;92:168–174
  8. Graham JB , Buckwalter JA , Hartley LJ , Brinkhous KM . Canine hemophilia (Observations on the course, the clotting anomaly, and the effects of blood transfusion) . J Exp Med . 1949;90:97–111
  9. Lozier JN , Dutra A , Pak E , Zhou N , Zheng Z , Nichols TC , et al.   The Chapel Hill hemophilia A dog colony exhibits an inversion of the factor VIII gene . Proc Natl Acad Sci USA . 2002;99:12991–12996
  10. Hough C , Kamisue S , Cameron C , Notley C , Tinlin S , Giles A , et al.   Aberrant splicing and premature termination of transcription of the FVIII gene as a cause of severe canine hemophilia A (Similarities with the intron 22 inversion mutation in human hemophilia) . Thromb Haemost . 2002;87:659–665
  11. Giles AR , Tinlin S , Greenwood R . A canine model of hemophilic (factor VIII:C deficiency) bleeding . Blood . 1982;60:727–730
  12. Lakich D , Kazazian HH , Antonarakis SE , Gitschier J . Inversions disrupting the factor VIII gene are a common cause of severe hemophilia A . Nat Genet . 1993;5:236–241
  13. Naylor JA , Brinke A , Hassock S , Green PM , Giannelli F . Characteristic mRNA abnormality found in half the patients with severe hemophilia A is due to large DNA inversions . Hum Mol Genet . 1993;2:1773–1773
  14. Antonarakis SE , Rossiter JP , Young M , Horst J , de Moerloose P , Sommer SS , et al.   Factor VIII gene inversions in severe hemophilia A (Results of an international consortium study) . Blood . 1995;86:2206–2212
  15. Levinson B , Bermingham JR , Metzenberg A , Kenwrick S , Chapman V , Gitschier J . Sequence of the human factor VIII-associated gene is conserved in mouse . Genomics . 1992;13:862–865
  16. Chao H , Mansfield SG , Bartel RC , Hiriyanna S , Mitchell LG , Garcia-Blanco MA , et al.   Phenotype correction of hemophilia A mice by spliceosome-mediated RNA trans-splicing . Nat Med . 2003;9:1015–1019
  17. Evans JP , Brinkhous KM , Brayer GD , Reisner HM , High KA . Canine hemophilia B resulting from a point mutation with unusual consequences . Proc Natl Acad Sci USA . 1989;86:10095–10099
  18. 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;84:352–354
  19. McCarthy K , Stewart P , Sigman J , Read M , Keith JC , Brinkhous KM , et al.   Pharmacokinetics of recombinant factor IX after intravenous and subcutaneous administration in dogs and cynomolgus monkeys . Thromb Haemost . 2002;87:824–830
  20. Herzog RW , Yang EY , Couto LB , Hagstrom JN , Elwell D , Fields PA , 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;5:56–63
  21. Snyder RO , Miao C , Meuse L , Tubb J , Donahue BA , Lin HF , et al.   Correction of hemophilia B in canine and murine models using recombinant adeno-associated viral vectors . Nat Med . 1999;5:64–70
  22. Chao H , Samulski RJ , Bellinger D , Monahan PE , Nichols T , Walsh C . Persistent expression of canine factor IX in hemophilia B canines . Gene Ther . 1999;6:1695–1704
  23. Ehrhardt A , Xu H , Dillow AM , Bellinger DA , Nichols TC , Kay MA . A gene-deleted adenoviral vector results in phenotypic correction of canine hemophilia B without liver toxicity or thrombocytopenia . Blood . 2003;102:2403–2411
  24. Monahan PE , Samulski RJ , Tazelaar J , Xiao X , Nichols TC , Bellinger DA , et al.   Direct intramuscular injection with recombinant AAV vectors results in sustained expression in a dog model of hemophilia . Gene Ther . 1998;5:40–49
  25. Wang L , Nichols TC , Read MS , Bellinger DA , Verma IM . Sustained expression of therapeutic level of factor IX in hemophilia B dogs by AAV-mediated gene therapy in liver . Mol Ther . 2000;1:154–158
  26. Mauser AE , Whitlark J , Whitney KM , Lothrop CD . A deletion mutation causes hemophilia B in Lhasa Apso dogs . Blood . 1996;88:3451–3455
  27. Mount JD , Herzog RW , Tillson DM , Goodman SA , Robinson N , McCleland ML , et al.   Sustained phenotypic correction of hemophilia B dogs with a factor IX null mutation by liver-directed gene therapy . Blood . 2002;99:2670–2676
  28. Andrews JL , Shirley PS , Iverson WO , Sherer AD , Markovits JE , King L , et al.   Evaluation of the duration of human factor VIII expression in nonhuman primates after systemic delivery of an adenoviral vector . Hum Gene Ther . 2002;13:1331–1336
  29. Lozier JN , Metzger ME , Donahue RE , Morgan RA . Adenovirus-mediated expression of human coagulation factor IX in the rhesus macaque is associated with dose-limiting toxicity . Blood . 1999;94:3968–3975
  30. Michou AI , Santoro L , Christ M , Julliard V , Pavirani A , Mehtali M . Adenovirus-mediated gene transfer (Influence of transgene, mouse strain and type of immune response on persistence of trangene expression) . Gene Ther . 1997;4:473–482
  31. Lozier J . The mouse MHC locus is the major genetic factor that controls the antibody response to human factor IX in mice . Blood . 2003;102:163a–164a
  32. Lozier JN , Metzger ME , Donahue RE , Morgan RA . The rhesus macaque as an animal model for hemophilia B gene therapy . Blood . 1999;93:1875–1881
  33. Lozier JN , Csako G , Mondoro TH , Krizek DM , Metzger ME , Costello R , et al.   Toxicity of a first-generation adenoviral vector in rhesus macaques . Hum Gene Ther . 2002;13:113–124
  34. Nathwani AC , Davidoff AM , Hanawa H , Hu Y , Hoffer FA , Nikanorov A , et al.   Sustained high-level expression of human factor IX (hFIX) after liver-targeted delivery of recombinant adeno-associated virus encoding the hFIX gene in rhesus macaques . Blood . 2002;100:1662–1669
  35. Colowick AB , Bohn RL , Avorn J , Ewenstein BM . Immune tolerance induction in hemophilia patients with inhibitors (Costly can be cheaper) . Blood . 2000;96:1698–1702
  36. Warrier I . Factor IX antibody and immune tolerance . Vox Sang . 1999;77(suppl 1):70–71
  37. Warrier I , Ewenstein BM , Koerper MA , Shapiro A , Key N , DiMichele D , et al.   Factor IX inhibitors and anaphylaxis in hemophilia B . J Pediatr Hematol Oncol . 1997;19:23–27
  38. Ewenstein BM , Takemoto C , Warrier I , Lusher J , Saidi P , Eisele J , et al.   Nephrotic syndrome as a complication of immune tolerance in hemophilia B . Blood . 1997;89:1115–1115
  39. Chao H , Walsh CE . Induction of tolerance to human factor VIII in mice . Blood . 2001;97:3311–3312
  40. Connelly S , Smith TAG , Dhir G , Gardner JM , Mehaffey MG , Zaret KS , et al.   In vivo gene delivery and expression of physiological levels of functional human factor VIII in mice . Hum Gene Ther . 1995;6:185–193
  41. Connelly S , Gardner JM , Lyons RM , McClelland A , Kaleko M . Sustained expression of therapeutic levels of human factor VIII in mice . Blood . 1996;87:4671–4677
  42. Connelly S , Mount J , Mauser A , Gardner JM , Kaleko M , McClelland A , et al.   Complete short-term correction of canine hemophilia A by in vivo gene therapy . Blood . 1996;88:3846–3853
  43. Connelly S , Andrews JL , Gallo AM , Kayda DB , Qian J , Hoyer L , et al.   Sustained phenotypic correction of murine hemophilia A by in vivo gene therapy . Blood . 1998;91:3273–3281
  44. Andrews JL , Kadan MJ , Gorziglia MI , Kaleko M , Connelly S . Generation and characterization of E1/E2a/E3/E4-deficient adenoviral vectors encoding human factor VIII . Mol Ther . 2001;3:329–336
  45. Bristol JA , Gallo-Penn A , Andrews J , Idamakanti N , Kaleko M , Connelly S . Adenovirus-mediated factor VIII gene expression results in attenuated anti-factor VIII-specific immunity in hemophilia A mice compared with factor VIII protein infusion . Hum Gene Ther . 2001;12:1651–1661
  46. Gallo-Penn AM , Shirley PS , Andrews JL , Tinlin S , Webster S , Cameron C , et al.   Systemic delivery of an adenoviral vector encoding canine factor VIII results in short-term phenotypic correction, inhibitor development, and biphasic liver toxicity in hemophilia A dogs . Blood . 2001;97:107–113
  47. Chuah MK , Schiedner G , Thorrez L , Brown B , Johnston M , Gillijns V , et al.   Therapeutic factor VIII levels and negligible toxicity in mouse and dog models of hemophilia A following gene therapy with high-capacity adenoviral vectors . Blood . 2003;101:1734–1743
  48. Balague C , Zhou J , Dai Y , Alemany R , Josephs SF , Andreason G , et al.   Sustained high-level expression of full-length human factor VIII and restoration of clotting activity in hemophilic mice using a minimal adenovirus vector . Blood . 2000;95:820–828
  49. Burton M , Nakai H , Colosi P , Cunningham J , Mitchell R , Couto L . Coexpression of factor VIII heavy and light chain adeno-associated viral vectors produces biologically active protein . Proc Natl Acad Sci USA . 1999;96:12725–12730
  50. Scallan CD , Liu T , Parker AE , Patarroyo-White SL , Chen H , Jiang H , et al.   Phenotypic correction of a mouse model of hemophilia A using AAV2 vectors encoding the heavy and light chains of FVIII . Blood . 2003;102:3919–3926
  51. Chao H , Sun L , Bruce A , Xiao X , Walsh CE . Expression of human factor VIII by splicing between dimerized AAV vectors . Mol Ther . 2002;5:716–722
  52. Sarkar R , Xiao W , Kazazian HH . A single adeno-associated virus (AAV)-murine factor VIII vector partially corrects the hemophilia A phenotype . J Thromb Haemost . 2003;1:220–226
  53. Scallan CD , Lillicrap D , Jiang H , Qian X , Patarroyo-White SL , Parker AE , et al.   Sustained phenotypic correction of canine hemophilia A using an adeno-associated viral vector . Blood . 2003;102:2031–2037
  54. Sarkar R , Tetreault R , Gao G , Wang L , Bell P , Chandler R , et al.   Total correction of hemophilia A mice with canine FVIII using an AAV 8 serotype . Blood . 2004;103:1253–1260
  55. Vandendriessche T , Vanslembrouck V , Goovaerts I , Zwinnen H , Vanderhaeghen ML , Collen D , 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;96:10379–10384
  56. Park F , Ohashi K , Kay MA . Therapeutic levels of human factor VIII and IX using HIV-1-based lentiviral vectors in mouse liver . Blood . 2000;96:1173–1176
  57. Smith TAG , Mehaffey MG , Kayda DB , Saunders JM , Yei S , Trapnell BC , et al.   Adenovirus mediated expression of therapeutic plasma levels of human factor IX in mice . Nat Genet . 1993;5:397–402
  58. Kay MA , Landen CN , Rothenberg SR , Taylor LA , Leland F , Wiehle S , et al.   In vivo hepatic gene therapy (Complete albeit transient correction of factor IX deficiency in hemophilia B dogs) . Proc Natl Acad Sci USA . 1994;91:2353–2357
  59. 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
  60. Herzog RW , Hagstrom JN , Kung S-H , Tai SJ , Wilson JM , Fisher KJ , 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
  61. Gui T , Lin HF , Jin DY , Hoffman M , Straight DL , Roberts HR , et al.   Circulating and binding characteristics of wild-type factor IX and certain Gla domain mutants in vivo . Blood . 2002;100:153–158
  62. Hagstrom JN , Couto LB , Scallan C , Burton M , McCleland ML , Fields PA , et al.   Improved muscle-derived expression of human coagulation factor IX from a skeletal actin/CMV hybrid enhancer/promoter . Blood . 2000;95:2536–2542
  63. High KA , Manno CS , Sabatino DE , et al.   Immune responses to AAV and to factor IX in a phase I study of AAV-mediated, liver-directed gene transfer for hemophilia B . Blood . 2003;102:154a–155a
  64. Arruda VR , Schuettrumpf J , Herzog RW , Nichols TC , Robinson N , Lotfi Y , 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
  65. Grimm D , Zhou S , Nakai H , Thomas CE , Storm TA , Fuess S , et al.   Preclinical in vivo evaluation of pseudotyped adeno-associated virus vectors for liver gene therapy . Blood . 2003;102:2412–2419
  66. Mingozzi F , Schuttrumpf J , Arruda VR , Liu Y , Liu YL , High KA , et al.   Improved hepatic gene transfer by using an adeno-associated virus serotype 5 vector . J Virol . 2002;76:10497–10502
  67. Roth DA , Tawa NE , O’Brien JM , Treco DA , Selden RF . Nonviral transfer of the gene encoding coagulation factor VIII in patients with severe hemophilia A . N Engl J Med . 2001;344:1735–1742
  68. Powell JS , Ragni MV , White GC , Lusher JM , Hillman-Wiseman C , Moon TE , et al.   Phase 1 trial of FVIII gene transfer for severe hemophilia A using a retroviral construct administered by peripheral intravenous infusion . Blood . 2003;102:2038–2045
  69. Greengard JS , Jolly DJ . Animal testing of retroviral-mediated gene therapy for factor VIII deficiency . Thromb Haemost . 1999;82:555–561
  70. Manno CS , Chew AJ , Hutchison S , Larson PJ , Herzog RW , Arruda VR , et al.   AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B . Blood . 2003;101:2963–2972
  71. Kay MA , Manno CS , Ragni MV , Larson PJ , Couto LB , McClelland A , et al.   Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector . Nat Genet . 2000;24:257–261
  72. Pruchnic R , Cao B , Peterson ZQ , Xiao X , Li J , Samulski RJ , et al.   The use of adeno-associated virus to circumvent the maturation-dependent viral transduction of muscle fibers . Hum Gene Ther . 2000;11:521–536
  73. Hacein-Bey-Abina S , Von Kalle C , Schmidt M , McCormack MP , Wulffraat N , Leboulch P , et al.   LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1 . Science . 2003;302:415–419

 The views expressed in this article are those of the author do not constitute FDA or US Federal Government policy.

PII: S0037-1963(04)00128-3

doi: 10.1053/j.seminhematol.2004.07.005

Seminars in Hematology
Volume 41, Issue 4 , Pages 287-296 , October 2004

Article Tools

* Image Usage & Resolution