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. 2020 Apr 28;4(4):CD010822.
doi: 10.1002/14651858.CD010822.pub4.

Gene therapy for haemophilia

Akshay Sharma  1 , Manu Easow Mathew  2 , Vasumathi Sriganesh  3 , Ulrike M Reiss  4
Affiliations

Gene therapy for haemophilia

Akshay Sharma et al. Cochrane Database Syst Rev. .

Abstract

Background: Haemophilia is a genetic disorder characterized by spontaneous or provoked, often uncontrolled, bleeding into joints, muscles and other soft tissues. Current methods of treatment are expensive, challenging and involve regular administration of clotting factors. Gene therapy for haemophilia is a curative treatment modality currently under investigation. This is an update of a published Cochrane Review.

Objectives: To evaluate the safety and efficacy of gene therapy for treating people with haemophilia A or B.

Search methods: We searched the Cochrane Cystic Fibrosis & Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews. Date of last search: 17 April 2020.

Selection criteria: Eligible trials include randomised or quasi-randomised clinical trials, including controlled clinical trials comparing gene therapy (with or without standard treatment) with standard treatment (factor replacement) or other 'curative' treatment such as stem cell transplantation for individuals with haemophilia A or B of all ages who do not have inhibitors to factor VIII or IX.

Data collection and analysis: No trials of gene therapy for haemophilia matching the inclusion criteria were identified.

Main results: No trials of gene therapy for haemophilia matching the inclusion criteria were identified.

Authors' conclusions: No randomised or quasi-randomised clinical trials of gene therapy for haemophilia were identified. Thus, we are unable to determine the safety and efficacy of gene therapy for haemophilia. Gene therapy for haemophilia is still in clinical investigation and there is a need for well-designed clinical trials to assess the long-term feasibility, success and risks of gene therapy for people with haemophilia.

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Conflict of interest statement

Akshay Sharma: none known. Manu Easow Mathew: none known. Vasumathi Sriganesh: is the Founder and Hon CEO of Quality Medical (QMed) Knowledge Foundation, a not‐for‐profit Trust in Mumbai, India. Through the Foundation she and her colleagues offer online courses, training and support for literature search, referencing and writing activities to health sciences students and professionals. Ulrike M Reiss: none known.

Figures

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1
PRISMA flow diagram showing process of study selection.
See this image and copyright information in PMC

Update of

References

Additional references

Anson 1984
    1. Anson DS, Choo KH, Rees DJ, Giannelli F, Gould K, Huddleston JA, et al. The gene structure of human anti-haemophilic factor IX. EMBO Journal 1984;3:1053-60. - PMC - PubMed
Aronstam 1993
    1. Aronstam A, Congard B, Evans DI, Gazengel CF, Herberg U, Hill FG, et al. HIV infection in haemophilia--a European cohort. Archives of Disease in Childhood 1993;68(4):521-4. [PMID: ] - PMC - PubMed
Bi 1995
    1. 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. Nature Genetics 1995;10(1):119-21. - PubMed
Brinkhous 1968
    1. Brinkhous KM, Shanbrom E, Roberts HR, Webster WP, Fekete L, Wagner RH. A new high-potency glycine-precipitated antihemophilic factor (AHF) concentrate. Treatment of classical hemophilia and hemophilia with inhibitors. JAMA 1968;205(9):613-7. - PubMed
Carcao 2014
    1. Carcao M. Changing paradigm of prophylaxis with longer acting factor concentrates. Haemophilia 2014;20 Suppl 4:99-105. [PMID: ] - PubMed
Castaman 2008
    1. Castaman G. Desmopressin for the treatment of haemophilia. Haemophilia 2008;14 Suppl 1:15-20. - PubMed
Choo 1982
    1. Choo KH, Gould KG, Rees DJ, Brownlee GG. Molecular cloning of the gene for human anti-haemophilic factor IX. Nature 1982;299(5879):178-80. - PubMed
Evatt 2006
    1. Evatt BL. The tragic history of AIDS in the hemophilia population, 1982-1984. Journal of Thrombosis and Haemostasis 2006;4(11):2295-301. - PubMed
George 2016
    1. George LA, Sullivan S, Teitel J, Cuker A, Luk A, Wright F, et al. Preliminary results of a phase 1/2 trial of SPK-9001, a hyperactive FIX variant delivered by a novel capsid, demonstrate consistent factor IX activity levels at the lowest dose cohort. Haemophilia 2016;22(Suppl 4):151-2. [DOI: 10.1111/hae.13068] - DOI
George 2017
    1. George LA, Sullivan SK, Giermasz A, Rasko JEJ, Samelson-Jones BJ, Ducore J, Cuker A, et al. Hemophilia B gene therapy with a high-specific-activity factor IX variant. New England Journal of Medicine 2017;377(23):2215-27. [DOI: 10.1056/NEJMoa1708538] [PMID: ] - DOI - PMC - PubMed
Gill 1983
    1. Gill JC, Menitove JE, Wheeler D, Aster RH, Montgomery RR. Generalized lymphadenopathy and T cell abnormalities in hemophilia A. Journal of Pediatrics 1983;103(1):18-22. [PMID: ] - PubMed
Gitschier 1984
    1. Gitschier J, Wood WI, Goralka TM, Wion KL, Chen EY, Eaton DH, et al. Characterization of the human factor VIII gene. Nature 1984;312:326-30. - PubMed
Goedert 1989
    1. Goedert JJ, Kessler CM, Aledort LM, Biggar RJ, Andes WA, White GC 2nd, et al. A prospective study of human immunodeficiency virus type 1 infection and the development of AIDS in subjects with hemophilia. New England Journal of Medicine 1989;321(17):1141-8. [PMID: ] - PubMed
Hacein‐Bey‐Abina 2003
    1. 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(5644):415-9. - PubMed
Hamed 2006
    1. Hamed SA. Drug evaluation: PTC-124--a potential treatment of cystic fibrosis and Duchenne muscular dystrophy. IDrugs 2006;9(11):783-9. [PMID: ] - PubMed
Higgins 2011a
    1. Higgins JPT, Altman DG, Sterne JAC, on behalf of the Cochrane Statistical Methods Group and the Cochrane Bias Methods Group. Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
Higgins 2011b
    1. Higgins JPT, Deeks JJ, Altman DG. Chapter 16: Special topics in statistics. In: Higgins JPT, Green S (editors). Cochrane Handbook of Systematic Reviews of Interventions. Version 5.1 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
High 2011
    1. High KA. Gene therapy for haemophilia: a long and winding road. Journal of Thrombosis and Haemostasis 2011;9 Suppl 1:2-11. - PubMed
Iorio 2011
    1. Iorio A, Marchesini E, Marcucci M, Stobart K, Chan AK. Clotting factor concentrates given to prevent bleeding and bleeding-related complications in people with hemophilia A or B. Cochrane Database of Systematic Reviews 2011, Issue 9. [DOI: 10.1002/14651858.CD003429.pub4] [PMID: ] - DOI - PubMed
Kasper 1972
    1. Kasper CK, Kipnis SA. Hepatitis and clotting-factor concentrates. JAMA 1972;221(5):510. [PMID: ] - PubMed
Konkle 2015
    1. Konkle BA, Stasyshyn O, Chowdary P, Bevan DH, Mant T, Shima M, et al. Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A. Blood 2015;126(9):1078-85. [DOI: 10.1182/blood-2015-03-630897] [PMID: ] - DOI - PMC - PubMed
Leissinger 2001
    1. Leissinger C, Becton D, Cornell C Jr, Cox Gill J. High-dose DDAVP intranasal spray (Stimate) for the prevention and treatment of bleeding in patients with mild haemophilia A, mild or moderate type 1 von Willebrand disease and symptomatic carriers of haemophilia A. Haemophilia 2001;7(3):258-66. - PubMed
Machin 2018
    1. Machin N, Ragni MV, Smith KJ. Gene therapy in hemophilia A: a cost-effectiveness analysis. Blood Advances 2018;2(14):1792-98. [PMID: ] - PMC - PubMed
Mahlangu 2018
    1. Mahlangu J, Oldenburg J, Paz-Priel I, Negrier C, Niggli M, Mancuso ME, et al. Emicizumab prophylaxis in patients who have hemophilia A without inhibitors. New England Journal of Medicine 2018;379(9):811-22. [DOI: 10.1056/NEJMoa1803550] [PMID: ] - DOI - PubMed
Makris 1990
    1. Makris M, Preston FE, Triger DR, Underwood JC, Choo QL, Kuo G, et al. Hepatitis C antibody and chronic liver disease in haemophilia. Lancet 1990;335(8698):1117-9. [PMID: ] - PubMed
Manco‐Johnson 2007
    1. Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. New England Journal of Medicine 2007;357(6):535-44. - PubMed
Manno 2003
    1. 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(8):2963-72. - PubMed
Manno 2006
    1. Manno CS, Pierce GF, Arruda VR, Glader B, Ragni M, Rasko JJ, et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nature Medicine 2006;12(3):342-7. - PubMed
Mannucci 1977
    1. Mannucci PM, Ruggeri ZM, Pareti FI, Capitanio A. 1-Deamino-8-d-arginine vasopressin: a new pharmacological approach to the management of haemophilia and von Willebrands' diseases. Lancet 1977;1(8017):869-72. [PMID: ] - PubMed
Miesbach 2018
    1. Miesbach W, Meijer K, Coppens M, Kampmann P, Klamroth R, Schutgens R, et al. Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B. Blood 2018;131(9):1022-31. [DOI: 10.1182/blood-2017-09-804419] [PMID: ] - DOI - PMC - PubMed
Miller 2005
    1. Miller DG, Trobridge GD, Petek LM, Jacobs MA, Kaul R, Russell DW. Large-scale analysis of adeno-associated virus vector integration sites in normal human cells. Journal of Virology 2005;79(17):11434-42. - PMC - PubMed
Mingozzi 2011
    1. Mingozzi F, High KA. Therapeutic in vivo gene transfer for genetic disease using AAV: progress and challenges. Nature Reviews. Genetics 2011;12(5):341-55. - PubMed
Nakai 2005
    1. Nakai H, Wu X, Fuess S, Storm TA, Munroe D, Montini E, et al. Large-scale molecular characterization of adeno-associated virus vector integration in mouse liver. Journal of Virology 2005;79(6):3606-14. - PMC - PubMed
Nathwani 2004
    1. Nathwani AC, Davidoff AM, Tuddenham EG. Prospects for gene therapy of haemophilia. Haemophilia 2004;10(4):309-18. - PubMed
Nathwani 2006
    1. Nathwani AC, Gray JT, Ng CY, Zhou J, Spence Y, Waddington SN, et al. Self-complementary adeno-associated virus vectors containing a novel liver-specific human factor IX expression cassette enable highly efficient transduction of murine and nonhuman primate liver. Blood 2006;107(7):2653-61. - PMC - PubMed
Nathwani 2011
    1. Nathwani AC, Tuddenham EG, Rangarajan S, Rosales C, McIntosh J, Linch DC, et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. New England Journal of Medicine 2011;365(25):2357-65. [PMID: ] - PMC - PubMed
Nathwani 2014
    1. Nathwani AC, Reiss UM, Tuddenham EG, Rosales C, Chowdary P, McIntosh J, et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. New England Journal of Medicine 2014;371(21):1994-2004. [DOI: 10.1056/NEJMoa1407309] [PMID: ] - DOI - PMC - PubMed
NCT00803205
    1. NCT00803205. Study of ataluren (PTC124™) in cystic fibrosis. //clinicaltrials.gov/ct2/show/study/NCT00803205 (accessed 1 September 2014). [NCT00803205]
NCT00847379
    1. NCT00847379. Phase 2b extension study of ataluren (PTC124) in Duchenne/Becker muscular dystrophy (DMD/BMD). //clinicaltrials.gov/ct2/show/NCT00847379 (accessed 1 September 2014). [NCT00847379]
NCT00947193
    1. NCT00947193. Study of ataluren (PTC124®) in hemophilia A and B. //clinicaltrials.gov/ct2/show/NCT00947193 (accessed 1 September 2014). [NCT00947193]
NCT00979238
    1. NCT00979238. An open label dose-escalation study of a self complementary adeno-associated viral vector (scAAV 2/8-LP1-hFIXco) for gene transfer in hemophilia B. //clinicaltrials.gov/show/NCT00979238 (accessed 26 April 2014). [NCT00979238]
NCT01687608
    1. NCT01687608. A phase 1/2 open-label, single ascending dose trial of a self-complementing optimized adeno-associated virus serotype 8 factor IX gene therapy (AskBio009) in adults with hemophilia B. //clinicaltrials.gov/show/NCT01687608 (accessed 26 April 2014). [NCT01687608]
NCT02396342
    1. NCT02396342. Trial of AAV5-hFIX in Severe or Moderately Severe Hemophilia B. //clinicaltrials.gov/ct2/show/NCT02396342 (accessed 05 November 2016). [NCT02396342]
NCT02484092
    1. NCT02484092. A Gene Therapy Study for Hemophilia B. //clinicaltrials.gov/ct2/show/NCT02484092 (accessed 05 November 2016). [NCT02484092]
NCT02576795
    1. NCT02576795. Gene Therapy Study in Severe Haemophilia A Patients. //clinicaltrials.gov/ct2/show/NCT02576795 (accessed 05 November 2016). [NCT02576795]
NCT02695160
    1. NCT02695160. Ascending Dose Study of Genome Editing by the Zinc Finger Protein (ZFP) Therapeutic SB-FIX in Severe Hemophilia B. //clinicaltrials.gov/ct2/show/NCT02695160 (accessed 05 November 2016). [NCT02695160]
NCT03001830
    1. NCT03001830. Gene Therapy for Haemophilia A. //clinicaltrials.gov/ct2/show/NCT03001830 (accessed 25 January 2019). [NCT03001830]
NCT03003533
    1. NCT03003533. A Gene Transfer Study for Hemophilia A. //clinicaltrials.gov/ct2/show/NCT03003533 (accessed 25 January 2019). [NCT03003533]
NCT03061201
    1. NCT03061201. Dose-Ranging Study of Recombinant AAV2/6 Human Factor 8 Gene Therapy SB-525 in Subjects With Severe Hemophilia A. //clinicaltrials.gov/ct2/show/NCT03061201 (accessed 25 January 2019). [NCT03061201]
NCT03217032
    1. NCT03217032. Gene Modified Stem Cells for Hemophelia A and B. //clinicaltrials.gov/ct2/show/NCT03217032 (accessed 25 January 2019). [NCT03217032]
NCT03369444
    1. NCT03369444. A Factor IX Gene Therapy Study (FIX-GT). //clinicaltrials.gov/ct2/show/NCT03369444 (accessed 25 January 2019). [NCT03369444]
NCT03370172
    1. NCT03370172. Safety and Dose Escalation Study of an Adeno-Associated Viral Vector for Gene Transfer in Hemophilia A Subjects. //clinicaltrials.gov/ct2/show/NCT03370172 (accessed 25 January 2019). [NCT03370172]
NCT03569891
    1. NCT03569891. HOPE-B: Trial of AMT-061 in Severe or Moderately Severe Hemophilia B Patients. //clinicaltrials.gov/ct2/show/NCT03569891 (accessed 25 January 2019). [NCT03569891]
NCT03588299
    1. NCT03588299. Factor VIII Gene Therapy Study in Patients With Hemophilia A. //clinicaltrials.gov/ct2/show/NCT03588299 (accessed 25 January 2019). [NCT03588299]
NCT03734588
    1. NCT03734588. Dose-finding Study of SPK-8016 Gene Therapy in Patients With Hemophilia A to Support Evaluation in Individuals With FVIII Inhibitors. //clinicaltrials.gov/ct2/show/NCT03734588 (accessed 25 January 2019). [NCT03734588]
NCT03818763
    1. NCT03818763. Gene Therapy Trial for Platelet Derived Factor VIII Production in Hemophilia A. //clinicaltrials.gov/ct2/show/NCT03818763 (accessed 25 January 2019). [NCT03818763]
NHF 2013
    1. National Hemophilia Foundation. Fast Facts. http://www.hemophilia.org/NHFWeb/MainPgs/MainNHF.aspx?menuid=259&con... (accessed 26 April 2014).
Palmer 1989
    1. Palmer TD, Thompson AR, Miller AD. Production of human factor IX in animals by genetically modified skin fibroblasts: potential therapy for hemophilia B. Blood 1989;73(2):438-45. - PubMed
Ponder 2008
    1. Ponder KP, Srivastava A. Walk a mile in the moccasins of people with haemophilia. Haemophilia 2008;14(3):618-20. - PubMed
Ponder 2011
    1. Ponder KP. Merry christmas for patients with hemophilia B. New England Journal of Medicine 2011;365(25):2424-5. - PubMed
Powell 2003
    1. Powell JS, Ragni MV, White GC 2nd, 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(6):2038-45. - PubMed
Powell 2013
    1. Powell JS, Pasi KJ, Ragni MV, Ozelo MC, Valentino LA, Mahlangu JN, et al. Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B. New England Journal of Medicine 2013;369(24):2313-23. [DOI: 10.1056/NEJMoa1305074] [PMID: ] - DOI - PubMed
Rangarajan 2017
    1. Rangarajan S, Walsh L, Lester W, Perry D, Madan B, Laffan M, et al. AAV5-factor VIII gene transfer in severe hemophilia A. New England Journal of Medicine 2017;377(26):2519-30. [DOI: 10.1056/NEJMoa1708483] [PMID: ] - DOI - PubMed
Roth 2001
    1. Roth DA, Tawa NE Jr, O'Brien JM, Treco DA, Selden RF, Factor VIII Transkaryotic Therapy Study Group. Nonviral transfer of the gene encoding coagulation factor VIII in patients with severe hemophilia A. New England Journal of Medicine 2001;344(23):1735-42. - PubMed
Santagostino 2010
    1. Santagostino E, Mancuso ME. Venous access in haemophilic children: choice and management. Haemophilia 2010;16 Suppl 1:20-4. [DOI: 10.1111/j.1365-2516.2009.02156.x] [PMID: ] - DOI - PubMed
Santagostino 2016
    1. Santagostino E, Martinowitz U, Lissitchkov T, Pan-Petesch B, Hanabusa H, Oldenburg J, et al. Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial. Blood 2016;127(14):1761-9. [DOI: 10.1182/blood-2015-09-669234] [PMID: ] - DOI - PMC - PubMed
Sterne 2011
    1. Sterne JAC, Egger M, Moher D, on behalf of the Cochrane Bias Methods Group. Chapter 10: Addressing reporting biases. In: Higgins JPT, Green S (editors). Cochrane Handbook forSystematic Reviews of Interventions Version 5.1 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
Toole 1984
    1. Toole JJ, Knopf JL, Wozney JM, Sultzman LA, Buecker JL, Pittman DD, et al. Molecular cloning of a cDNA encoding human antihaemophilic factor. Nature 1984;312(5992):342-7. - PubMed
Tuddenham 2012
    1. Tuddenham E. Gene therapy for haemophilia B. Haemophilia 2012;18 Suppl 4:13-7. - PubMed
VandenDriessche 1999
    1. 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. Proceedings of the National Academy of Sciences of the United States of America 1999;96(18):10379-84. - PMC - PubMed
Webster 1965
    1. Webster WP, Roberts HR, Thelin GM, Wagner RH, Brinkhous KM. Clinical use of a new glycine-precipitated antihemophilic fraction. American Journal of the Medical Sciences 1965;250(6):643-51. - PubMed
WFH 2013
    1. World Federation of Hemophilia. Annual Report 2013. http://www1.wfh.org/publications/files/pdf-1578.pdf (accessed 02 December 2016).
Wong 2011
    1. Wong T, Recht M. Current options and new developments in the treatment of haemophilia. Drugs 2011;71(3):305-20. - PubMed
Xu 2003
    1. Xu L, Gao C, Sands MS, Cai SR, Nichols TC, Bellinger DA, et al. Neonatal or hepatocyte growth factor-potentiated adult gene therapy with a retroviral vector results in therapeutic levels of canine factor IX for hemophilia B. Blood 2003;101(10):3924-32. - PubMed
Young 2015
    1. Young G, Mahlangu J, Kulkarni R, Nolan B, Liesner R, Pasi J et al. Recombinant factor VIII Fc fusion protein for the prevention and treatment of bleeding in children with severe hemophilia A. Journal of Thrombosis and Haemostasis 2015;13(6):967-77. [DOI: 10.1111/jth.12911] [PMID: ] - DOI - PubMed

References to other published versions of this review

Sharma 2014
    1. Sharma A, Easow Mathew M, Sriganesh V, Neely JA, Kalipatnapu S. Gene therapy for haemophilia. Cochrane Database of Systematic Reviews 2014, Issue 11. [DOI: 10.1002/14651858.CD010822.pub2] - DOI - PubMed
Sharma 2016
    1. Sharma A, Mathew ME, Sriganesh V, Reiss UM. Gene therapy for haemophilia. Cochrane Database of Systematic Reviews 2016, Issue 12. [DOI: 10.1002/14651858.CD010822.pub3] [PMID: ] - DOI - PMC - PubMed

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