Gene therapy for haemophilia: an update on progress in clinical trials

Sarah Gilgunn

doi:10.17225/jhp.00039

Abstract

Abstract

Clotting factor replacement therapy has proven a highly effective means of treating haemophilia A and B. But treatment involves frequent and lifelong infusion of factor concentrates and is generally prophylactic rather than curative. It is also extremely expensive, associated with inhibitor formation and does not fully abolish the potential for spontaneous bleeding. Gene therapy offers a potential cure for haemophilia, with the possible continuous expression of a clotting factor gene following the administration of a viral vector carrying the appropriate gene. Recent clinical trials of gene therapy for haemophilia have proven positive in selected patients and new studies are underway.

Article

View Full Article

References

1. Cancio MI, Reiss UM, Nathwani AC, et al. Developments in the treatment of hemophilia B: focus on emerging gene therapy. Appl Clin Genet 2013; 6: 91-101. doi: 10.2147/TACG.S31928.
2. Gringeri A, Ewenstein B, Reininger A. The burden of bleeding in haemophilia: is one bleed too many? Haemophilia 2014; 20(4): 459-63. doi: 10.1111/hae.12375.
3. Schrijvers LH, Uitslager N, Schuurmans MJ, Fischer K.Barriers and motivators of adherence to prophylactic treatment in haemophilia: a systematic review. Haemophilia 2013 5; 19(3): 355-6. doi: 10.1111/hae.12079.
4. Kaufman RJ, Powell JS. Molecular approaches for improved clotting factors for haemophilia. Hematology Am Soc Hematol Educ Program 2013; 2013: 30-6. doi: 10.1182/asheducation-2013.1.30.
5. Chuah MK, Evens H, VandenDriessche T. Gene therapy for hemophilia. J Thromb Haemost 2013; 11 Suppl 1: 99-110. doi: 10.1111/jth.12215.
6. Porada CD, Stem C, Almeida-Porada G. Gene Therapy; The promise of a permanent cure. NC Med J 2013; 74(6): 526-9.
7. 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; 5(1): 64-70.
8. Mount JD, Herzog RW, Tillson DM, et al. Sustained phenotypic correction of hemophilia B dogs with a factor IX null mutation by liver-directed gene therapy. Blood 2002; 99(8): 2670-6.
9. High KA. The gene therapy journey for hemophilia: are we there yet? Blood 2012; 120(23): 4482-7. doi: 10.1182/blood-2012-05-423210.
10. Mingozzi F, High KA. Immune responses to AAV vectors: overcoming barriers to successful gene therapy Blood 2013; 122(1): 23-36. doi: 10.1182/blood-2013-01-306647.
11. Roth DA, Tawa NE, O’Brien JM, et al. Nonviral transfer of the gene encoding coagulation factor VIII in patients with severe haemophilia A. N Engl J Med 2001; 344(23): 1735–1742.
12. Powell JS, Ragni MV, White GC, et al. Phase 1 trial of FVIII gene transfer for severe haemophilia A using a retroviral construct administered by peripheral intravenous infusion. Blood 2003; 102(6): 2038–2045.
13. White GC, Monahan PE. Gene therapy for haemophilia A. In: Lee CA, Berntorp EE, Hoots K, editors. Textbook of Haemophilia. 2nd ed. Hoboken, NJ: Wiley-Blackwell; 2005.
14. Manno CS, Chew AJ, Hutchison S, et al. AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe haemophilia B. Blood 2003; 101(8): 2963–2972
15. Manno CS, Pierce GF, Arruda VR, et al. Successful transduction of liver in haemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med 2006; 12(3): 342–347.
16. Nathwani AC, Tuddenham EG, Rangarajan S, et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med 2011; 365: 2357-65. doi: 10.1056/NEJMoa1108046.
17. 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: 1994-2004. doi: 10.1056/NEJMoa1407309.
18. http://www.fda.gov/
19. Pick A, Gilbert K, McCaul J. The role of effective communication in achieving informed consent for clinical trials. Nurs Stand 2014 Nov 5;29(10):45-8. doi: 10.7748/ns.29.10.45.e9443.

PDF Download

Download PDF

Open in full-page viewer

Authors

Sarah Gilgunn

sgilgunn@mail.dcu.ie

Board of directors, Irish Haemophilia Society and molecular biologist, School of Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland