Gene Therapy of Hemophilia

ABSTRACT

Hemophilia A and B are X-linked bleeding disorders caused by mutations within the factor VIII and factor IX genes, respectively. Although both disorders can be easily treated by substitution with concentrates of functional factor VIII and factor IX, considerable effort has been undertaken to develop a gene therapy for hemophilia in order to improve patients' life quality and reduce high costs of therapy. The principle of gene therapy is the introduction of an intact copy of the factor VIII/factor IX gene in somatic cells, compensating for the defective gene. To do this, retroviral, adenoviral, and adeno-associated virus (AAV) vector systems, among others, were used. Encouraged by the results of preliminary experiments using preponderant mouse and canine models, three clinical phase I studies on hemophilia A and B patients have been initiated, one of which has been preliminarily reported successful.

KEYWORD

Hemophilia A - hemophilia B - gene therapy - animal models - human clinical protocols

REFERENCES

• 1 Giannelli F, Reen P M, Sommer S S. Haemophilia B: database of point mutations and short additions and deletions-eight edition.  Nucleic Acids Res . 1998;  26 265-268
• 2 Kemball-Cook G, Tuddenham E GD, Wacey A I. The factor VIII structure and mutation resource site: HAMSTERS, version 4.  Nucleic Acids Res . 1998;  26 216-219
• 3 Brackmann H H, Hofmann P, Etzel F, Egli H. Home care of hemophilia in West Germany.  Thromb Haemost . 1976;  35 544-552
• 4 Jones P K, Ratnoff O D. The changing prognosis of classic hemophilia (factor VIII ``deficiency'').  Ann Intern Med . 1991;  114 641-648
• 5 Spero J A, Lewis J H, van Thiel H D, Hasiba U, Rabin B S. Asymptomatic structural liver disease in hemophilia.  N Engl J Med . 1978;  298 1371-1378
• 6 Esteban J I, Esteban R, Viladomiu C. Hepatitis C virus antibodies among risk groups in Spain.  Lancet . 1988;  II 294-297
• 7 Goedert J J, Sarngadharan M G, Eyster M E. Antibodies reactive with human T cell leukemia viruses in the serum of hemophiliacs receiving factor VIII concentrate.  Blood . 1985;  65 492-495
• 8 White G, Shapiro A, Ragni M. Clinical evaluation of recombinant factor IX.  Semin Hematol . 1998;  35 33-38
• 9 Bray G L, Gomperts E D, Courter S. A multicenter study of recombinant factor VIII (Recombinate): safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. The Recombinante Study Group.  Blood . 1994;  83 2428-2435
• 10 Lusher J M. Inhibitors in young boys with haemophilia.  Baillieres Best Pract Res Clin Haematol . 2000;  13 457-468
• 11 Brackmann H H, Oldenburg J, Schwaab R. Immune tolerance for the treatment of factor VIII inhibitors-twenty years Bonn Protocol.  Vox Sang . 1996;  70(Suppl 1) 30-35
• 12 Yao S N, Kurachi K. Expression of human factor IX in mice after injection of genetically modified myoblasts.  Proc Natl Acad Sci USA . 1992;  89 3357-3361
• 13 Palmer T D, Thompson A R, Miller A D. Production of human factor IX in animals by genetically modified skin fibroblasts: potential therapy for hemophilia B.  Blood . 1989;  73 438-445
• 14 Yao S N, Wilson J M, Nabel E G. Expression of human factor IX in rat capillary endothelial cells: toward somatic gene therapy for hemophilia B.  Proc Natl Acad Sci USA . 1991;  88 8101-8105
• 15 Gu W, Brooks M, Catalfamo J, Ray J, Ray K. Two distinct mutations cause severe hemophilia B in two unrelated canine pedigrees.  Thromb Haemost . 1999;  82 1270-1275
• 16 Greengard J S, Jolly D J. Animal testing of retroviral-mediated gene therapy for factor VIII deficiency.  Thromb Haemost . 1999;  82 555-561
• 17 Kundu R K, Sangiori F, Wu L Y. Targeted inactivation of the coagulation factor IX gene causes hemophilia B in mice.  Blood . 1998;  92 168-174
• 18 Kren B T, Bandyopadhyay P, Steer C J. In vivo site-directed mutagenesis of the factor IX gene by chimeric RNA/DNA oligonucleotides.  Nat Med . 1998;  4 285-290
• 19 Templeton N S, Lasic D D. New directions in liposome gene delivery.  Mol Biotechnol . 1999;  11 175-180
• 20 Recchia A, Parks R J, Lamartina S. Site-specific integration mediated by a hybrid adenovirus/adeno-associated virus vector.  Proc Natl Acad Sci USA . 1999;  96 2615-2620
• 21 St. Louis D, Verma I M. An alternative approach to somatic cell gene therapy.  Proc Natl Acad Sci USA . 1988;  85 3150-3154
• 22 Chen L, Nelson D M, Zheng Z, Morgan R A. Ex vivo fibroblast transduction in rabbits results in long-term (>600 days) factor IX expression in a small percentage of animals.  Hum Gene Ther . 1998;  9 2341-2351
• 23 Hurwitz D R, Kirchgesser M, Merrill W. Systemic delivery of human growth hormone or human factor IX in dogs by reintroduced genetically modified autologous bone marrow stromal cells.  Hum Gene Ther . 1997;  8 137-156
• 24 Dai Y, Roman M, Naviaux R K, Verma I M. Gene therapy via primary myoblasts: long term expression of factor IX protein following transplantation in vivo.  Proc Natl Acad Sci USA . 1992;  89 10892-10895
• 25 Yao S, Smith K J, Kurachi K. Primary myoblast-mediated gene transfer: persistent expression of human factor IX in mice.  Gene Ther . 1994;  1 99-107
• 26 Wang J M, Zheng H, Blaivas M, Kurachi K. Persistent systemic production of human factor IX in mice by skeletal myoblast-mediated gene transfer: feasibility of repeat application to obtain therapeutic levels.  Blood . 1997;  90 1075-1082
• 27 Palmer T D, Rosman G J, Osborne W AR, Miller A D. Genetically modified skin fibroblasts persist long after transplantation but gradually inactivate introduced genes.  Proc Natl Acad Sci USA . 1991;  88 1330-1334
• 28 Challita P, Skelton D, El-Khoueiry A. Multiple modifications in cis elements of the long terminal repeat of retroviral vectors lead to increased expression and decreased DNA methylation in embryonic carcinoma cells.  J Virol . 1995;  69 748-755
• 29 Hoeben R C, Fallaux F J, Cramer S J. Expression of the blood-clotting factor-VIII cDNA is repressed by a transcriptional silencer located in its coding region.  Blood . 1995;  85 2447-2454
• 30 Lynch C M, Israel D I, Kaufman R J, Miller A D. Sequences in the coding region of clotting factor VIII act as dominant inhibitors of RNA accumulation and protein production.  Hum Gene Ther . 1993;  4 259-272
• 31 Hoeben R C, Einerhand M PW, Briet E. Toward gene therapy in haemophilia A: retrovirus-mediated transfer of factor VIII gene into murine haematopoeitic progenitor cells.  Thromb Haemost . 1992;  67 341-345
• 32 Hurwitz D R, Cherington V, Rubin H. Ex vivo gene therapy of hemophilia A and B using bone marrow stromal cells in a canine model.  Proc Am Soc Gene Ther . 1998;  3 Abst
• 33 Smith T A, Mehaffey M G, Kayda D B. Adenovirus mediated expression of therapeutic plasma levels of human factor IX in mice.  Nat Genet . 1993;  5 397-402
• 34 Poller W, Schneider-Rasp S, Liebert U. Stabilization of transgene expression by incorporation of E3 region genes into an adenoviral factor IX vector and by transient anti-CD4 treatment of the host.  Gene Ther . 1996;  3 521-530
• 35 Herzog R W, Hagstrom J N, Kung S H. 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
• 36 Monahan P E, Samulski R J, Tazelaar J. Direct intramuscular injection with recombinant AAV vectors results in sustained expression in a dog model of hemophilia.  Gene Ther . 1998;  5 40-49
• 37 Connelly S, Smith T AG, Dhir G. In vivo delivery and expression of physiological levels of functional human factor VIII in mice.  Hum Gene Ther . 1995;  6 185-193
• 38 Connelly S, Andrews J L, Gallo A M. Sustained phenotypic correction of murine hemophilia A by in vivo gene therapy.  Blood . 1998;  91 3272-3281
• 39 van den Driessche T, Vanslembrouck V, Goovaerts I. 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
• 40 Connelly S, Mount J, Mauser A. Complete short-term correction of canine hemophilia A by in vivo gene therapy.  Blood . 1996;  88 3846-3853
• 41 Kay M A, Rothenberg S, Landen C N. In vivo gene therapy of hemophilia B: sustained partial correction in factor IX-deficient dogs.  Science . 1993;  262 117-119
• 42 Kay M A, Landen C N, Rothenberg S R. 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
• 43 Snyder R O, Miao C, Meuse L. Correction of hemophilia B in canine and murine models using recombinant adeno-associated viral vectors.  Nat Med . 1999;  5 64-70
• 44 Herzog R W, Yang E Y, Couto L B. 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
• 45 Kaufman R J. Advances toward gene therapy for hemophilia at the millennium.  Hum Gene Ther . 1999;  10 2091-2107
• 46 Schwaab R, Brackmann H H, Meyer C. Haemophilia A: mutation type determines risk of inhibitor formation.  Thromb Haemost . 1995;  74 1402-1406
• 47 Kay M A, Manno C S, Ragni M V. Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector.  Nat Genet . 2000;  24 257-261
• 48 Park F, Ohashi K, Kay M A. Therapeutic levels of human factor VIII and IX using HIV-1-based lentiviral vectors in mouse liver.  Blood . 2000;  96 1173-1176
• 49 Kochanek S. Development of high-capacity adenoviral vectors for gene therapy.  Thromb Haemost . 1999;  82 547-551
• 50 Caplen N J, Higginbotham J N, Scheel J R. Adeno-retroviral chimeric viruses as in vivo transducing agents.  Gene Ther . 1999;  6 454-459