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DOI: 10.1055/s-2004-825637
Hemophilia Gene Transfer: Comparison with Conventional Protein Replacement Therapy
Publication History
Publication Date:
07 May 2004 (online)
One of the unanswered questions in hemophilia is whether gene transfer, if successful, will be a safe and effective alternative to standard clotting factor treatment for hemophilia. Despite life-threatening complications of protein-based clotting factor treatment during the last three decades, including acquired immunodeficiency syndrome and hepatitis C, factor infusion is now considered safe, effective, and compatible with a normal lifespan. Thus, protein-based therapy will be the standard against which the safety and efficacy of gene transfer will be judged. Will the potential risks of gene transfer be sufficiently low to justify its use? Should all individuals with hemophilia consider gene transfer? To answer these questions, the known risks and benefits of current protein-based therapy must be compared with the potential risks and benefits of gene transfer. It is anticipated that risks of gene transfer may include the known risks of protein-based therapies, including allergic reactions, inflammatory responses, inhibitor formation, chronic hepatitis, as well as gene-transfer-specific risks, including germline transmission, insertional mutagenesis, thrombosis, and potential ethical and psychological issues. This article reviews and compares the risks and benefits of standard protein-based therapy with those of gene transfer, and considers how gene transfer might fit into state-of-the-art management of hemophilia.
KEYWORDS
Gene therapy - hemophilia - potential risks - factor replacement
REFERENCES
- 1 Hoyer L W. Hemophilia A. N Engl J Med. 1994; 330 39-47
- 2 Mannucci P M, Tuddenheim E GD. Medical progress: the hemophilias-from royal genes to gene therapy. N Engl J Med. 2001; 344 1773-1779
- 3 Ragni M V. New generation recombinant factor concentrates: bridge to gene therapy. Haemophilia. 2001; 7(suppl 1) 28-35
- 4 Schlesinger K W, Ragni M V. Safety of the new-generation recombinant factor concentrates. Expert Opin Drug Safety. 2002; 1 213-223
- 5 Roth D A, Tawa N E, O’Brien J M, Treco D A, Selden R F. Nonviral transfer of the gene encoding coagulation factor VIII in patients with severe hemophilia A. N Engl J Med. 2001; 344 1735-1742
- 6 Roth D A, Treco D A. A phase 1 study of nonviral ex vivo factor VIII gene transfer in 12 severe hemophilia A study subjects. Paper presented at: Sixth NHF Workshop on Gene Therapies for Hemophilia; April 26, 2003 Salk Institute La Jolla, CA; 2003: 30
- 7 Manno C S, Chew A H, Hutchison S et al.. AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood. 2003; 101 2963-2972
- 8 Powell J S, Ragni M V, White G C 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
- 9 Glader B, Kay M A, Hutchison S A et al.. A phase I trial of AAV-mediated, liver-directed gene transfer for hemophilia B. Paper presented at: Sixth NHF Workshop on Gene Therapies for Hemophilia; April 26, 2003 Salk Institute La Jolla, CA; 2003: 31
- 10 White G C. Clinical trial results with MaxAdFVIII, a gutless adenovirus vector driving liver-specific expression of full-length factor VIII. Paper presented at: Sixth NHF Workshop on Gene Therapies for Hemophilia; April 26, 2003 Salk Institute La Jolla, CA; 2003
- 11 Lillicrap D, James P, Poon M C, Rivard G. Suppression of nonsense mutations in severe hemophilia A and B. Paper presented at Sixth NHF Workshop on Gene Therapies for Hemophilia; April 26, 2003 Salk Institute La Jolla, CA; 2003: 33
- 12 Manco-Johnson M J, Nuss R, Geraghty S, Funk S, Kilcoyne R. Results of secondary prophylaxis in children with severe hemophilia. Am J Hematol. 1994; 47 113-117
- 13 Lofquist T, Nilsson I M, Berntorp E et al.. Haemophilia prophylaxis in young patients: a long term followup. J Intern Med. 1997; 241 395-400
- 14 Soucie J M, Nuss R, Evatt B et al.. Mortality among males with hemophilia: relations with source of medical care. Blood. 2000; 96 437-442
- 15 Ragni M V, Hord J D, Blatt J. Central venous catheter infection in hemophiliacs undergoing prophylaxis or immune tolerance. Haemophilia. 1997; 3 90-95
- 16 Journeycake J M, Quinn C T, Miller K L, Zajac J L, Buchanan G R. Catheter-related deep venous thrombosis in children with hemophilia. Blood. 2001; 98 1727-1731
- 17 Medical & Scientific Advisory Committee (MASAC) .Recommendations regarding factor shortage. Advisory 114 New York; National Hemophilia Foundation November, 2001
- 18 Ehrenforth S, Kreuz W, Scharrer I et al.. Incidence of development of factor VIII and factor IX inhibitors in haemophilics. Lancet. 1992; 339 594-599
- 19 Warrier I, Ewenstein B, Koerper M et al.. Factor IX inhibitors and anaphylaxis in hemophilia B. J Pediatr Hematol Oncol. 1997; 19 23-27
- 20 Addiego J, Kasper C, Abildgaard C et al.. Frequency of inhibitor development in haemophiliacs treated with low-purity factor VIII. Lancet. 1993; 342 462-464
- 21 Schwaab R, Brackman H H, Meyer C et al.. Haemophilia A: mutation type determines risk of inhibitor formation. Thromb Haemost. 1995; 74 1402-1406
- 22 Ragni M V, Belle S H. Impact of human immunodeficiency virus (HIV) on progression to end-stage liver disease in individuals with hemophilia and hepatitis C. J Infect Dis. 2001; 183 1112-1115
- 23 Rosendaal F R, Varekamp I, Smit C et al.. Mortality and course of death in Dutch hemophiliacs 1973-86. Br J Haematol. 1989; 71 71-76
- 24 Ragni M V, Belle S H, Im K et al.. Survival in HIV-infected liver transplant recipients. J Infect Dis. 2003; 188 1412-1420
- 25 Ragni M V, Amato D A, Lofaro M L et al.. Randomized study of didanosine monotherapy and combination therapy with zidovudine in hemophilic and non-hemophilic subjects with asymptomatic HIV-1 infection. Blood. 1995; 85 2337-2346
- 26 Sulkowski M S, Thomas D L, Chaisson R E, Moore R D. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA. 2000; 283 74-80
- 27 Lusher J M. Thrombogenicity associated with factor IX complex concentrates. Semin Hematol. 1991; 28(suppl 6) 3-5
- 28 Robinson K L, Savoia H, Street A M. Thrombotic complications in two patients receiving NovoSeven. Haemophilia. 2000; 349 17
- 29 Alsolaiman M M, Chang K, Arjomand H, Costacurta G. Acute left anterior descending artery occlusion in a hemophiliac A patient during recombinant factor VIII infusion: treatment with coronary angioplasty. Catheter Cardiovasc Interv. 2000; 50 468-472
- 30 Lozier J N, Csako G, Mondoro T H et al.. Toxicity of a first-generation adenoviral vector in rhesus macaques. Hum Gene Ther. 2002; 13 113-124
- 31 Chirmule N, Propert K, Magosin S, Qian Y, Qian R, Wilson J. Immune responses to adenovirus and adeno-associated virus in humans. Gene Ther. 1999; 6 1574-1583
- 32 Herzog R W, Mount J D, Arruda V R et al.. Muscle-directed gene transfer and transient immune suppression result in sustained partial correction of canine hemophilia B caused by a null mutation. Mol Ther. 2001; 4 192-200
- 33 High K A. Gene transfer as an approach to treating hemophilia. Semin Thromb Hemostas. 2003; 29 107-120
- 34 Herzog R W, Mingozzi F, Dobrzynski E. Induction of immune tolerance to secreted transgene products by hepatic AAV-mediated gene transfer. Paper presented at: Sixth NHF Workshop on Gene Therapies for Hemophilia April 26, 2003 Salk Institute La Jolla, CA; 24
- 35 Matsumoto K, Fuji H, Michalopoulis G, Fung J J, Demetris A J. Human biliary epithelial cells secrete and respond to cytokines and hepatocyte growth factors: IL-6 HGF, and EGF promote DNA synthesis in vitro. Hepatology. 1994; 20 376-382
- 36 Tilg H, Diehl A. Cytokines in alcoholic and nonalcoholic steatohepatitis. N Engl J Med. 2000; 343 1467-1476
- 37 Schiedner G, Bloch W, Hertel S et al.. Intravenous adenovirus vector particles cause Kupffer cell mediated activation of endothelial cells. Paper presented at: Sixth NHF Workshop on Gene Therapies for Hemophilia; April 25, 2003 Salk Institute La Jolla, CA; 2003: 18
- 38 Hacein-Bey-Abina S, von Kalle C, Le Deist F et al.. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med. 2003; 348 255-256
- 39 Rumley A, Lowe G DO, Sneetnam P M et al.. Factor VIII, von Willebrand factor and the risk of major ischaemic heart disease in the Caerphilly Heart Study. Br J Haematol. 1999; 105 110-116
- 40 Kazazian H H. An estimated frequency of endogenous insertional mutations in humans. Nat Genet. 1999; 22 130
- 41 Roehl H H, Liebbrandt M E, Greengard J S 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 germline transduction. Hum Gene Ther. 2000; 11 2529-2540
- 42 Arruda V R, Fields P A, Milner R et al.. Lack of germline transmission of vector sequences following systemic administration of recombinant AAV-2 vector in males. Mol Ther. 2001; 4 586-592
- 43 Noguchi P. Risks and benefits of gene therapy. N Engl J Med. 2003; 348 193-194
- 44 King N MP. Informed consent in hemophilia gene transfer research. Paper presented at: Sixth NHF Workshop on Gene Therapies for Hemophilia April 26, 2003 Salk Institute La Jolla, CA; 2003: 34
- 45 Chen D T, Miller G F, Rosenstein D L. Clinical research and the physician-patient relationship. Ann Intern Med. 2003; 138 669-672
- 46 DiMichele D, Miller F G, Finns J J. Gene therapy ethics and haemophilia: an inevitable therapeutic future?. Haemophilia. 2003; 9 145-152
Margaret V RagniM.D. M.P.H.
Division Hematology, Oncology, University of Pittsburgh School of Medicine
Hemophilia Center Western PA
3636 Boulevard of the Allies
Pittsburgh, PA 15213-4306
Email: ragni@msx.dept-med.pitt.edu