Reviews
4 September 2024
Vol. 3 No. 2 (2024)
The evolving landscape of gene therapy for congenital severe hemophilia: a 2024 state of the art
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
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Despite major advances in prophylaxis, no repeated dosing regimen with currently employed extended-half-life or non-factor products replaces the advantages of a long-term cure in persons with severe congenital hemophilia A and B (HA, HB). They indeed live with the risk of breakthrough bleedings, and treatment is still invasive, both physically and psychologically. Early studies showed that adeno-associated virus-based in vivo gene therapy (AAV-based in vivo GT), could convert hemophilia persons from a severe to mild a phenotype for years. However, the proportion of the hemophilia population likely to benefit from this transformative strategy was uncertain. Current evidence is expanding the eligibility criteria, and helps to predict risks, complications and unexpected side effects of this advanced treatment. Thus, among future options, AAV-based in vivo GT is likely to become the treatment of choice in HA and HB, if real-life data confirm its negligible short-term adverse events. However, while the global use of AAV-based in vivo GT is endorsed as a key objective of future studies in hemophilia, the liberating capability of a potentially one-off treatment on individuals with chronic diseases for whom lifelong cure has been inaccessible so far remains to be thoroughly recognized by government bodies. This is critical for reimbursement agencies to absorb the cost of the cure and calls for a partnership between health care systems and the pharmaceutical industry. However, bridging the gap between the costs of the advanced treatments approved for commercialization and their readiness to persons with HA and HB is still a challenging task.
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High KA. Turning genes into medicines - what have we learned from gene therapy drug development in the past decade? Nat Commun 2020;11:5821. DOI: https://doi.org/10.1038/s41467-020-19507-0
Mendell JR, Al-Zaidy SA, Rodino-Klapac LR, al. Current clinical applications of in vivo gene therapy with AAVs. Mol Ther 2021;29:464-88. DOI: https://doi.org/10.1016/j.ymthe.2020.12.007
Flotte TR, Afione SA, Zeitlin PL. Adeno-associated virus vector gene expression occurs in nondividing cells in the absence of vector DNA integration. Am J Respir Cell Mol Biol 1994;11:517-21. DOI: https://doi.org/10.1165/ajrcmb.11.5.7946381
Crenshaw BJ, Jones LB, Bell CR, et al. Perspective on Adenoviruses: epidemiology, pathogenicity, and gene therapy. Biomedicines. 2019;7. DOI: https://doi.org/10.3390/biomedicines7030061
Keeler AM, Flotte TR. Recombinant adeno-associated virus gene therapy in light of luxturna (and zolgensma and glybera): where are we, and how did we get here? Annu Rev Virol 2019;6:601-21. DOI: https://doi.org/10.1146/annurev-virology-092818-015530
Di Minno G, Miesbach W, Castaman G, Peyvandi F. Next-generation strategies to improve safety and efficacy of adeno-associated virus-based gene therapy for hemophilia: lessons from clinical trials in other gene therapies. Haematologica. 2024 Mar 7. [Online ahead of print] DOI: https://doi.org/10.3324/haematol.2023.284622
Peyvandi F, Garagiola I. Clinical advances in gene therapy updates on clinical trials of gene therapy in hemophilia. Hemophilia 2019;25:738-46. DOI: https://doi.org/10.1111/hae.13816
Spadarella G, Di Minno A, Brunetti-Pierri N, et al. The evolving landscape of gene therapy for congenital hemophilia: An unprecedented, problematic but promising opportunity for worldwide clinical studies. Blood Rev 2021;46:100737. DOI: https://doi.org/10.1016/j.blre.2020.100737
Nijdam A, Altisent C, Carcao MD, et al. Bleeding before prophylaxis in severe hemophilia: paradigm shift over two decades. Haematologica 2015;100:e84-6. DOI: https://doi.org/10.3324/haematol.2014.115709
Oldenburg J, Dolan G, Lemm G. Hemophilia care then, now and in the future. Hemophilia 2009;15:2-7. DOI: https://doi.org/10.1111/j.1365-2516.2008.01946.x
Mannucci PM. Treatment of hemophilia: building on strength in the third millennium. Hemophilia 2011;17:1-24. DOI: https://doi.org/10.1111/j.1365-2516.2011.02657.x
Nijdam A, Kurnik K, Liesner R, et al. How to achieve full prophylaxis in young boys with severe hemophilia A: different regimens and their effect on early bleeding and venous access. Hemophilia 2015;21:444-50. DOI: https://doi.org/10.1111/hae.12613
Mannucci PM. Hemophilia therapy: the future has begun. Haematologica 2020;105:545-53. DOI: https://doi.org/10.3324/haematol.2019.232132
Chorba TL, Holman RC, Clarke MJ, Evatt BL. Effects of HIV infection on age and cause of death for persons with hemophilia A in the United States. Am J Hematol 2001;66:229-40. DOI: https://doi.org/10.1002/ajh.1050
Plug I, Van Der Bom JG, Peters M, et al. Mortality and causes of death in patients with hemophilia, 1992-2001: a prospective cohort study. J Thromb Haemost 2006;4:510-6. DOI: https://doi.org/10.1111/j.1538-7836.2006.01808.x
Tagliaferri A, Rivolta GF, Iorio A, et al. Mortality and causes of death in Italian persons with hemophilia, 1990-2007. Hemophilia 2010;16:437-46. DOI: https://doi.org/10.1111/j.1365-2516.2009.02188.x
Khair K, Ranta S, Thomas A, Lindvall K. The impact of clinical practice on the outcome of central venous access devices in children with hemophilia. Hemophilia 2017;23:e276-e81. DOI: https://doi.org/10.1111/hae.13241
Di Minno A, Spadarella G, Nardone A, et al. Attempting to remedy sub-optimal medication adherence in hemophilia: the rationale for repeated ultrasound visualisations of the patient's joint status. Blood Rev 2019;33:106-16. DOI: https://doi.org/10.1016/j.blre.2018.08.003
Iorio A, Marchesini E, Marcucci M, et al. Clotting factor concentrates given to prevent bleeding and bleeding-related complications in people with hemophilia A or B. Cochrane Database Syst Rev 2011:CD003429. DOI: https://doi.org/10.1002/14651858.CD003429.pub4
Balkaransingh P, Young G. Novel therapies and current clinical progress in hemophilia A. Ther Adv Hematol 2018;9:49-61. DOI: https://doi.org/10.1177/2040620717746312
Carvalhosa AM, Henrard S, Lambert C, Hermans C. Physical and mental quality of life in adult patients with hemophilia in Belgium: the impact of financial issues. Hemophilia 2014;20:479-85. DOI: https://doi.org/10.1111/hae.12341
Chen SL. Economic costs of hemophilia and the impact of prophylactic treatment on patient management. Am J Manag Care 2016;22:s126-33.
Miesbach W, O'Mahony B, Key NS, Makris M. How to discuss gene therapy for hemophilia? A patient and physician perspective. Hemophilia 2019;25:545-57. DOI: https://doi.org/10.1111/hae.13769
Wiley RE, Khoury CP, Snihur AWK, et al. From the voices of people with hemophilia A and their caregivers: Challenges with current treatment, their impact on quality of life and desired improvements in future therapies. Hemophilia 2019;25:433-40. DOI: https://doi.org/10.1111/hae.13754
Lee Mortensen G, Strand AM, Almen L. Adherence to prophylactic haemophilic treatment in young patients transitioning to adult care: a qualitative review. Hemophilia 2018;24:862-72. DOI: https://doi.org/10.1111/hae.13621
Thornburg CD, Duncan NA. Treatment adherence in hemophilia. Patient Prefer Adherence 2017;11:1677-86. DOI: https://doi.org/10.2147/PPA.S139851
Olivieri M, Kurnik K, Pfluger T, Bidlingmaier C. Identification and long-term observation of early joint damage by magnetic resonance imaging in clinically asymptomatic joints in patients with hemophilia A or B despite prophylaxis. Hemophilia 2012;18:369-74. DOI: https://doi.org/10.1111/j.1365-2516.2011.02682.x
Arruda VR, Doshi BS, Samelson-Jones BJ. Novel approaches to hemophilia therapy: successes and challenges. Blood 2017;130:2251-6. DOI: https://doi.org/10.1182/blood-2017-08-742312
Weyand AC, Pipe SW. New therapies for hemophilia. Blood 2019;133:389-98. DOI: https://doi.org/10.1182/blood-2018-08-872291
Jiménez-Yuste V, Auerswald G, Benson G, et al. Achieving and maintaining an optimal trough level for prophylaxis in hemophilia: the past, the present and the future. Blood Transf 2014;12:314-9.
Dodd C, Watts RG. A comparison of traditional vs. Canadian tailored prophylaxis dosing of prophylactic factor infusions in children with hemophilia A and B in a single hemophilia treatment center. Hemophilia 2012;18:561-7. DOI: https://doi.org/10.1111/j.1365-2516.2011.02741.x
Krishnan S, Vietri J, Furlan R, Duncan N. Adherence to prophylaxis is associated with better outcomes in moderate and severe hemophilia: results of a patient survey. Hemophilia 2015;21:64-70. DOI: https://doi.org/10.1111/hae.12533
Kraft J, Blanchette V, Babyn P, et al. Magnetic resonance imaging and joint outcomes in boys with severe hemophilia A treated with tailored primary prophylaxis in Canada. J Thromb Haemost 2012;10:2494-502. DOI: https://doi.org/10.1111/jth.12025
Seuser A, Bohm P, Wermes C. Early orthopaedic challenges in hemophilia patients and therapeutic approach. Thromb Res 2014;134:S61-7. DOI: https://doi.org/10.1016/j.thromres.2013.10.022
Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007;357:535-44. DOI: https://doi.org/10.1056/NEJMoa067659
Mazepa MA, Monahan PE, Baker JR, et al. Men with severe hemophilia in the United States: birth cohort analysis of a large national database. Blood 2016;127:3073-81. DOI: https://doi.org/10.1182/blood-2015-10-675140
Oladapo AO, Epstein JD, Williams E, et al. Health-related quality of life assessment in hemophilia patients on prophylaxis therapy: a systematic review of results from prospective clinical trials. Hemophilia 2015;21:e344-58. DOI: https://doi.org/10.1111/hae.12759
Di Minno MN, Ambrosino P, Quintavalle G, et al. Assessment of hemophilic arthropathy by ultrasound: where do we stand? Semin Thromb Hemost 2016;42:541-9. DOI: https://doi.org/10.1055/s-0036-1579640
Lak M, Peyvandi F, Mannucci PM. Clinical manifestations and complications of childbirth and replacement therapy in 385 Iranian patients with type 3 von Willebrand disease. Br J Haematol 2000;111:1236-9. DOI: https://doi.org/10.1046/j.1365-2141.2000.02507.x
Mannucci PM, Cortesi PA, Di Minno MND, et al. Comparative analysis of the pivotal studies of extended half-life recombinant FVIII products for treatment of hemophilia A. Hemophilia 2021;27:e422-e33. DOI: https://doi.org/10.1111/hae.14313
Santoro C, Di Minno MND, Corcione A, et al. Improving assessment and management of pain in hemophilia: an Italian Delphi consensus statement. Blood Rev 2022;51:100885. DOI: https://doi.org/10.1016/j.blre.2021.100885
Blamey G, Buranahirun C, Buzzi A, et al. Hemophilia and sexual health: results from the HERO and B-HERO-S studies. Patient Relat Outcome Meas 2019;10:243-55. DOI: https://doi.org/10.2147/PROM.S211339
Cassis FR, Buzzi A, Forsyth A, et al. Hemophilia Experiences, Results and Opportunities (HERO) study: influence of hemophilia on interpersonal relationships as reported by adults with hemophilia and parents of children with hemophilia. Hemophilia 2014;20:e287-95.
Cassis FR, Querol F, Forsyth A, Iorio A, Board HIA. Psychosocial aspects of hemophilia: a systematic review of methodologies and findings. Hemophilia 2012;18:e101-14. DOI: https://doi.org/10.1111/j.1365-2516.2011.02683.x
Tagliaferri A, Franchini M, Rivolta GF, et al. Pain assessment and management in hemophilia: a survey among Italian patients and specialist physicians. Hemophilia 2018;24:766-73. DOI: https://doi.org/10.1111/hae.13600
Witkop M, Neff A, Buckner TW, al. Self-reported prevalence, description and management of pain in adults with hemophilia: methods, demographics and results from the Pain, Functional Impairment, and Quality of life (P-FiQ) study. Hemophilia 2017;23:556-65. DOI: https://doi.org/10.1111/hae.13214
Auerswald G, Dolan G, Duffy A, et al. Pain and pain management in hemophilia. Blood Coagul Fibrinolysis 2016;27:845-54. DOI: https://doi.org/10.1097/MBC.0000000000000571
Salzman R, Cook F, Hunt T, et al. Addressing the value of gene therapy and enhancing patient access to transformative treatments. Mol Ther 2018;26:2717-26. DOI: https://doi.org/10.1016/j.ymthe.2018.10.017
Witkop ML, Lambing A, Nichols CD, et al. Interrelationship between depression, anxiety, pain, and treatment adherence in hemophilia: results from a US cross-sectional survey. Patient Prefer Adherence 2019;13:1577-87. DOI: https://doi.org/10.2147/PPA.S212723
Davari M, Gharibnaseri Z, Ravanbod R, Sadeghi A. Health status and quality of life in patients with severe hemophilia A: a cross-sectional survey. Hematol Rep 2019;11:7894. DOI: https://doi.org/10.4081/hr.2019.7894
Mahlangu J, Oldenburg J, Callaghan MU, et al. Health-related quality of life and health status in persons with hemophilia A with inhibitors: a prospective, multicentre, non-interventional study (NIS). Hemophilia 2019;25:382-91. DOI: https://doi.org/10.1111/hae.13731
O'Hara J, Walsh S, Camp C, et al. The impact of severe hemophilia and the presence of target joints on health-related quality-of-life. Health Qual Life Outcomes 2018;16:84. DOI: https://doi.org/10.1186/s12955-018-0908-9
Machin N, Ragni MV. Measuring success in hemophilia gene therapy using a factor level and outcomes yardstick. Expert Rev Hematol 2018;11:83-6. DOI: https://doi.org/10.1080/17474086.2018.1423961
Coppola A, Di Minno MN, Santagostino E. Optimizing management of immune tolerance induction in patients with severe hemophilia A and inhibitors: towards evidence-based approaches. Br J Haematol 2010;150:515-28. DOI: https://doi.org/10.1111/j.1365-2141.2010.08263.x
Kempton CL, White GC, 2nd. How we treat a hemophilia A patient with a factor VIII inhibitor. Blood 2009;113:11-7. DOI: https://doi.org/10.1182/blood-2008-06-160432
Lusher JM, Scharrer I. Evolution of recombinant factor VIII safety: KOGENATE and Kogenate FS/Bayer. Int J Hematol 2009;90:446-54. DOI: https://doi.org/10.1007/s12185-009-0435-x
Oladapo AO, Lu M, Walsh S, et al. Inhibitor clinical burden of disease: a comparative analysis of the CHESS data. Orphanet J Rare Dis 2018;13:198. DOI: https://doi.org/10.1186/s13023-018-0929-9
Aledort L, Bullinger M, von Mackensen S, et al. Why should we care about quality of life in persons with hemophilia? Hemophilia 2012;18:e154-7. DOI: https://doi.org/10.1111/j.1365-2516.2012.02771.x
O'Mahony B, Noone D, Prihodova L. Survey of coagulation factor concentrates tender and procurement procedures in 38 European Countries. Hemophilia 2015;21:436-43. DOI: https://doi.org/10.1111/hae.12720
Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Guidelines for the management of hemophilia. Hemophilia 2013;19:e1-47. DOI: https://doi.org/10.1111/j.1365-2516.2012.02909.x
Ljung R, Auerswald G, Benson G, et al. Inhibitors in hemophilia A and B: management of bleeds, inhibitor eradication and strategies for difficult-to-treat patients. Eur J Haematol 2019;102:111-22. DOI: https://doi.org/10.1111/ejh.13193
Di Minno G, Castaman G, De Cristofaro R, et al. Progress, and prospects in the therapeutic armamentarium of persons with congenital hemophilia. Defining the place for liver-directed gene therapy. Blood Rev 2023;58:101011. DOI: https://doi.org/10.1016/j.blre.2022.101011
Mannucci PM, Kessler CM, Germini F, et al. Bleeding events in people with congenital hemophilia A without factor VIII inhibitors receiving prophylactic factor VIII treatment: a systematic literature review. Hemophilia 2023;29:954-62. DOI: https://doi.org/10.1111/hae.14803
Maria A, Alessandro C, Declan N, Peyvandi F. Hemorrhagic and thrombotic adverse events associated with emicizumab and extended half-life factor VIII replacement drugs: EudraVigilance data of 2021. J Thromb Haemost 2023;21:546-52. DOI: https://doi.org/10.1016/j.jtha.2023.01.010
Kitazawa T, Esaki K, Tachibana T, et al. Factor VIIIa-mimetic cofactor activity of a bispecific antibody to factors IX/IXa and X/Xa, emicizumab, depends on its ability to bridge the antigens. Thrombosis Haemostasis 2017;117:1348-57. DOI: https://doi.org/10.1160/TH17-01-0030
Kitazawa T, Igawa T, Sampei Z, et al. A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model. Nat Med 2012;18:1570-4. DOI: https://doi.org/10.1038/nm.2942
Mahlangu J. Emicizumab for the prevention of bleeds in hemophilia A. Exp Opin Biol Ther 2019;19:753-61. DOI: https://doi.org/10.1080/14712598.2019.1626370
Ferla R, Alliegro M, Dell'Anno M, et al. Low incidence of hepatocellular carcinoma in mice and cats treated with systemic adeno-associated viral vectors. Mol Ther Methods Clin Dev 2021;20:247-57. DOI: https://doi.org/10.1016/j.omtm.2020.11.015
Kuzmin DA, Shutova MV, Johnston NR, et al. The clinical landscape for AAV gene therapies. Nat Rev Drug Discov 2021;20:173-4. DOI: https://doi.org/10.1038/d41573-021-00017-7
Miesbach W, Meijer K, Coppens M, et al. Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B. Blood 2018;131:1022-31. DOI: https://doi.org/10.1182/blood-2017-09-804419
Nathwani AC. Gene therapy for hemophilia. Hematology Am Soc Hematol Educ Program 2022:569-78. DOI: https://doi.org/10.1182/hematology.2022000388
Manno CS, Pierce GF, Arruda VR, et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med 2006;12:342-7. DOI: https://doi.org/10.1038/nm1358
Doshi BS, Arruda VR. Gene therapy for hemophilia: what does the future hold? Ther Adv Hematol 2018;9:273-93. DOI: https://doi.org/10.1177/2040620718791933
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: https://doi.org/10.1056/NEJMoa1407309
van der Loo JC, Wright JF. Progress and challenges in viral vector manufacturing. Hum Mol Genet 2016;25:R42-52. DOI: https://doi.org/10.1093/hmg/ddv451
George LA, Ragni MV, Rasko JEJ, et al. Long-term follow-up of the first in human intravascular delivery of AAV for gene transfer: AAV2-hFIX16 for severe hemophilia B. Mol Ther 2020;28:2073-82. DOI: https://doi.org/10.1016/j.ymthe.2020.06.001
Boutin S, Monteilhet V, Veron P, et al. Prevalence of serum IgG and neutralizing factors against adeno-associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: implications for gene therapy using AAV vectors. Hum Gene Ther 2010;21:704-12. DOI: https://doi.org/10.1089/hum.2009.182
Klamroth R, Hayes G, Andreeva T, et al. Global seroprevalence of pre-existing immunity against AAV5 and other AAV serotypes in people with hemophilia A. Hum Gene Ther 2022;33:432-41. DOI: https://doi.org/10.1089/hum.2021.287
Pipe S, Leebeek FWG, Ferreira V, et al. Clinical considerations for capsid choice in the development of liver-targeted AAV-based gene transfer. Mol Ther Methods Clin Dev 2019;15:170-8. DOI: https://doi.org/10.1016/j.omtm.2019.08.015
Patton KS, Harrison MT, Long BR, et al. Monitoring cell-mediated immune responses in AAV gene therapy clinical trials using a validated IFN-gamma ELISpot method. Mol Ther Methods Clin Dev 2021;22:183-95. DOI: https://doi.org/10.1016/j.omtm.2021.05.012
Kotterman MA, Schaffer DV. Engineering adeno-associated viruses for clinical gene therapy. Nat Rev Genet 2014;15:445-51. DOI: https://doi.org/10.1038/nrg3742
Ozelo MC, Mahlangu J, Pasi KJ, et al. Valoctocogene roxaparvovec gene therapy for hemophilia A. N Engl J Med 2022;386:1013-25. DOI: https://doi.org/10.1056/NEJMoa2113708
Ozelo MC, Mahlangu J, Pasi J, et al. Efficacy and safety of valoctocogene roxaparvovec adeno‐associated virus gene transfer for severe hemophilia A: results from the phase 3 GENEr8‐1 trial. Oral presentation at ISTH 2021 congress. Res Pract Thromb Haemost 2021;5:e12591.
Fong S, Yates B, Sihn CR, et al. Interindividual variability in transgene mRNA and protein production following adeno-associated virus gene therapy for hemophilia A. Nat Med 2022;28:789-97. DOI: https://doi.org/10.1038/s41591-022-01751-0
Schmidt M, Foster GR, Coppens M, et al. Molecular evaluation and vector integration analysis of HCC complicating AAV gene therapy for hemophilia B. Blood Adv 2023;7:4966-9. DOI: https://doi.org/10.1182/bloodadvances.2023009876
George LA, Sullivan SK, Giermasz A, et al. Hemophilia B gene therapy with a high-specific-activity factor IX variant. N Engl J Med 2017;377:2215-27. DOI: https://doi.org/10.1056/NEJMoa1708538
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: https://doi.org/10.1056/NEJMoa1108046
Rangarajan S, Walsh L, Lester W, et al. AAV5-factor VIII gene transfer in severe hemophilia A. N Engl J Med 2017;377:2519-30. DOI: https://doi.org/10.1056/NEJMoa1708483
Konkle BA, Walsh CE, Escobar MA, et al. BAX 335 hemophilia B gene therapy clinical trial results: potential impact of CpG sequences on gene expression. Blood 2021;137:763-74. DOI: https://doi.org/10.1182/blood.2019004625
Pierce GF. Uncertainty in an era of transformative therapy for hemophilia: addressing the unknowns. Hemophilia 2021;27:103-13. DOI: https://doi.org/10.1111/hae.14023
Nathwani AC, Rosales C, McIntosh J, et al. Long-term safety and efficacy following systemic administration of a self-complementary AAV vector encoding human FIX pseudotyped with serotype 5 and 8 capsid proteins. Mol Ther 2011;19:876-85. DOI: https://doi.org/10.1038/mt.2010.274
Pasi KJ, Rangarajan S, Mitchell N, et al. Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for hemophilia A. N Engl J Med 2020;382:29-40. DOI: https://doi.org/10.1056/NEJMoa1908490
Conti F, Buonfiglioli F, Scuteri A, et al. Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals. J Hepatol 2016;65:727-33. DOI: https://doi.org/10.1016/j.jhep.2016.06.015
Qvigstad C, Tait RC, Rauchensteiner S, et al. The elevated prevalence of risk factors for chronic liver disease among ageing people with hemophilia and implications for treatment. Medicine (Baltimore) 2018;97:e12551. DOI: https://doi.org/10.1097/MD.0000000000012551
Llovet JM, Villanueva A. Liver cancer: effect of HCV clearance with direct-acting antiviral agents on HCC. Nat Rev Gastroenterol Hepatol 2016;13:561-2. DOI: https://doi.org/10.1038/nrgastro.2016.140
Han MAT. Noninvasive tests (NITs) for hepatic fibrosis in fatty liver syndrome. Life (Basel) 2020;10. DOI: https://doi.org/10.3390/life10090198
Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005;112:2735-52. DOI: https://doi.org/10.1161/CIRCULATIONAHA.105.169404
Venkatesh SK, Yin M, Ehman RL. Magnetic resonance elastography of liver: technique, analysis, and clinical applications. J Magn Reson Imaging 2013;37:544-55. DOI: https://doi.org/10.1002/jmri.23731
Shah AG, Lydecker A, Murray K, et al. Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2009;7:1104-12. DOI: https://doi.org/10.1016/j.cgh.2009.05.033
Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 2007;45:846-54. DOI: https://doi.org/10.1002/hep.21496
Hordeaux J, Buza EL, Jeffrey B, et al. MicroRNA-mediated inhibition of transgene expression reduces dorsal root ganglion toxicity by AAV vectors in primates. Sci Transl Med 2020;12. DOI: https://doi.org/10.1126/scitranslmed.aba9188
Hetz C, Zhang K, Kaufman RJ. Mechanisms, regulation and functions of the unfolded protein response. Nat Rev Mol Cell Biol 2020;21:421-38. DOI: https://doi.org/10.1038/s41580-020-0250-z
Pipe SW, Gonen-Yaacovi G, Segurado OG. Hemophilia A gene therapy: current and next-generation approaches. Exp Opin Biol Ther 2022;22:1099-115. DOI: https://doi.org/10.1080/14712598.2022.2002842
Ghemrawi R, Khair M. Endoplasmic reticulum stress and unfolded protein response in neurodegenerative diseases. Int J Mol Sci 2020;21. DOI: https://doi.org/10.3390/ijms21176127
Prasad V, Greber UF. The endoplasmic reticulum unfolded protein response - homeostasis, cell death and evolution in virus infections. FEMS Microbiol Rev 2021;45. DOI: https://doi.org/10.1093/femsre/fuab016
Rietveld IM, Lijfering WM, le Cessie S, et al. High levels of coagulation factors and venous thrombosis risk: strongest association for factor VIII and von Willebrand factor. J Thromb Haemost 2019;17:99-109. DOI: https://doi.org/10.1111/jth.14343
Simioni P, Tormene D, Tognin G, et al. X-linked thrombophilia with a mutant factor IX (factor IX Padua). N Engl J Med 2009;361:1671-5. DOI: https://doi.org/10.1056/NEJMoa0904377
Pierce GF, Iorio A. Past, present and future of hemophilia gene therapy: From vectors and transgenes to known and unknown outcomes. Hemophilia 2018;24:60-7. DOI: https://doi.org/10.1111/hae.13489
Naso MF, Tomkowicz B, Perry WL, 3rd, Strohl WR. Adeno-associated virus (AAV) as a vector for gene therapy. BioDrugs 2017;31:317-34. DOI: https://doi.org/10.1007/s40259-017-0234-5
Samelson-Jones BJ, George LA. Adeno-associated virus gene therapy for hemophilia. Annu Rev Med 2023;74:231-47. DOI: https://doi.org/10.1146/annurev-med-043021-033013
Consortium EH. BioMarin announced an additional serious adverse event in its gene therapy clinical trial for hemophilia A. 2022 Available from: https://www.ehc.eu/biomarin-announced-an-additional-serious-adverse-event-in-its-gene-therapy-clinical-trial-for-hemophilia-a/
Donsante A, Miller DG, Li Y, et al. AAV vector integration sites in mouse hepatocellular carcinoma. Science 2007;317:477. DOI: https://doi.org/10.1126/science.1142658
Hatada I, Morita S, Obata Y, et al. Identification of a new imprinted gene, Rian, on mouse chromosome 12 by fluorescent differential display screening. J Biochem 2001;130:187-90. DOI: https://doi.org/10.1093/oxfordjournals.jbchem.a002971
Nakai H, Montini E, Fuess S, et al. AAV serotype 2 vectors preferentially integrate into active genes in mice. Nat Genet 2003;34:297-302. DOI: https://doi.org/10.1038/ng1179
Chandler RJ, LaFave MC, Varshney GK, et al. Vector design influences hepatic genotoxicity after adeno-associated virus gene therapy. J Clin Invest 2015;125:870-80. DOI: https://doi.org/10.1172/JCI79213
La Bella T, Imbeaud S, Peneau C, et al. Adeno-associated virus in the liver: natural history and consequences in tumour development. Gut 2020;69:737-47. DOI: https://doi.org/10.1136/gutjnl-2019-318281
Nault JC, Datta S, Imbeaud S, et al. Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas. Nat Genet 2015;47:1187-93. DOI: https://doi.org/10.1038/ng.3389
Chandler RJ, LaFave MC, Varshney GK, et al. Genotoxicity in mice following AAV gene delivery: a safety concern for human gene therapy? Mol Ther 2016;24:198-201. DOI: https://doi.org/10.1038/mt.2016.17
Nguyen GN, Everett JK, Kafle S, et al. A long-term study of AAV gene therapy in dogs with hemophilia A identifies clonal expansions of transduced liver cells. Nat Biotechnol 2021;39:47-55. DOI: https://doi.org/10.1038/s41587-020-0741-7
Greig JA, Martins KM, Breton C, et al. Integrated vector genomes may contribute to long-term expression in primate liver after AAV administration. Nat Biotechnol 2023 Nov 6. [Online ahead of print]. DOI: https://doi.org/10.1038/s41587-023-01974-7
Goedert JJ, Chen BE, Preiss L, et al. Reconstruction of the hepatitis C virus epidemic in the US hemophilia population, 1940-1990. Am J Epidemiol 2007;165:1443-53. DOI: https://doi.org/10.1093/aje/kwm030
Svicher V, Cento V, Bernassola M, et al. Novel HBsAg markers tightly correlate with occult HBV infection and strongly affect HBsAg detection. Antivir Res 2012;93:86-93. DOI: https://doi.org/10.1016/j.antiviral.2011.10.022
LoDuca PA, Hoffman BE, Herzog RW. Hepatic gene transfer as a means of tolerance induction to transgene products. Curr Gene Ther 2009;9:104-14. DOI: https://doi.org/10.2174/156652309787909490
Crudele JM, Finn JD, Siner JI, et al. AAV liver expression of FIX-Padua prevents and eradicates FIX inhibitor without increasing thrombogenicity in hemophilia B dogs and mice. Blood 2015;125:1553-61. DOI: https://doi.org/10.1182/blood-2014-07-588194
Finn JD, Nichols TC, Svoronos N, et al. The efficacy and the risk of immunogenicity of FIX Padua (R338L) in hemophilia B dogs treated by AAV muscle gene therapy. Blood 2012;120:4521-3. DOI: https://doi.org/10.1182/blood-2012-06-440123
Finn JD, Ozelo MC, Sabatino DE, et al. Eradication of neutralizing antibodies to factor VIII in canine hemophilia A after liver gene therapy. Blood 2010;116:5842-8. DOI: https://doi.org/10.1182/blood-2010-06-288001
Mingozzi F, Hasbrouck NC, Basner-Tschakarjan E, et al. Modulation of tolerance to the transgene product in a nonhuman primate model of AAV-mediated gene transfer to liver. Blood 2007;110:2334-41. DOI: https://doi.org/10.1182/blood-2007-03-080093
Arruda VR, Samelson-Jones BJ. Gene therapy for immune tolerance induction in hemophilia with inhibitors. J Thromb Haemost 2016;14:1121-34. DOI: https://doi.org/10.1111/jth.13331
Ragni MV, George LA, Members of working group tNSotSWofViGanbffr. The national blueprint for future factor VIII inhibitor clinical trials: NHLBI State of the Science (SOS) Workshop on factor VIII inhibitors. Hemophilia 2019;25:581-9. DOI: https://doi.org/10.1111/hae.13717
Gringeri A, Mantovani LG, Scalone L, et al. Cost of care and quality of life for patients with hemophilia complicated by inhibitors: the COCIS study group. Blood 2003;102:2358-63. DOI: https://doi.org/10.1182/blood-2003-03-0941
Carcao M, Escuriola-Ettingshausen C, Santagostino E, et al. The changing face of immune tolerance induction in hemophilia A with the advent of emicizumab. Hemophilia 2019;25:676-84. DOI: https://doi.org/10.1111/hae.13762
Gollomp KL, Doshi BS, Arruda VR. Gene therapy for hemophilia: progress to date and challenges moving forward. Transfus Apher Sci 2019;58:602-12. DOI: https://doi.org/10.1016/j.transci.2019.08.012
Di Minno G, Coppola A, Margaglione M, et al. Predictors of inhibitor eradication by primary immune tolerance induction in severe hemophilia A with high responding inhibitors. Hemophilia 2022;28:55-64. DOI: https://doi.org/10.1111/hae.14431
Hay CR, DiMichele DM, International Immune Tolerance S. The principal results of the International Immune Tolerance study: a randomized dose comparison. Blood 2012;119:1335-44. DOI: https://doi.org/10.1182/blood-2011-08-369132
Mimuro J, Mizukami H, Shima M, Matsushita T, Taki M, Muto S, et al. The prevalence of neutralizing antibodies against adeno-associated virus capsids is reduced in young Japanese individuals. J Med Virol 2014;86:1990-7. DOI: https://doi.org/10.1002/jmv.23818
Monahan PE, Negrier C, Tarantino M, et al. Emerging immunogenicity and genotoxicity considerations of adeno-associated virus vector gene therapy for hemophilia. J Clin Med 2021;10. DOI: https://doi.org/10.3390/jcm10112471
Ertl HCJ, High KA. Impact of AAV capsid-specific t-cell responses on design and outcome of clinical gene transfer trials with recombinant adeno-associated viral vectors: an evolving controversy. Hum Gene Ther 2017;28:328-37. DOI: https://doi.org/10.1089/hum.2016.172
Pipe SW, Leebeek FWG, Recht M, et al. Gene therapy with etranacogene dezaparvovec for hemophilia B. N Engl J Med 2023;388:706-18. DOI: https://doi.org/10.1056/NEJMoa2211644
Chiorini JA, Afione S, Kotin RM. Adeno-associated virus (AAV) type 5 Rep protein cleaves a unique terminal resolution site compared with other AAV serotypes. J Virol 1999;73:4293-8. DOI: https://doi.org/10.1128/JVI.73.5.4293-4298.1999
Gao G, Vandenberghe LH, Wilson JM. New recombinant serotypes of AAV vectors. Curr Gene Ther 2005;5:285-97. DOI: https://doi.org/10.2174/1566523054065057
Halbert CL, Miller AD, McNamara S, et al. Prevalence of neutralizing antibodies against adeno-associated virus (AAV) types 2, 5, and 6 in cystic fibrosis and normal populations: implications for gene therapy using AAV vectors. Hum Gene Ther 2006;17:440-7. DOI: https://doi.org/10.1089/hum.2006.17.440
Majowicz A, Nijmeijer B, Lampen MH, et al. Therapeutic hFIX activity achieved after single AAV5-hFIX treatment in hemophilia B patients and NHPs with pre-existing anti-AAV5 NABs. Mol Ther Methods Clin Dev 2019;14:27-36. DOI: https://doi.org/10.1016/j.omtm.2019.05.009
Leborgne C, Barbon E, Alexander JM, et al. IgG-cleaving endopeptidase enables in vivo gene therapy in the presence of anti-AAV neutralizing antibodies. Nat Med 2020;26:1096-101. DOI: https://doi.org/10.1038/s41591-020-0911-7
Corti M, Elder M, Falk D, et al. B-cell depletion is protective against anti-AAV capsid immune response: a human subject case study. Mol Ther Methods Clin Dev 2014;1. DOI: https://doi.org/10.1038/mtm.2014.33
Unzu C, Hervas-Stubbs S, Sampedro A, et al. Transient and intensive pharmacological immunosuppression fails to improve AAV-based liver gene transfer in non-human primates. J Translat Med 2012;10:122. DOI: https://doi.org/10.1186/1479-5876-10-122
Monteilhet V, Saheb S, Boutin S, et al. A 10 patient case report on the impact of plasmapheresis upon neutralizing factors against adeno-associated virus (AAV) types 1, 2, 6, and 8. Mol Ther 2011;19:2084-91. DOI: https://doi.org/10.1038/mt.2011.108
Buchlis G, Podsakoff GM, Radu A, et al. Factor IX expression in skeletal muscle of a severe hemophilia B patient 10 years after AAV-mediated gene transfer. Blood 2012;119:3038-41. DOI: https://doi.org/10.1182/blood-2011-09-382317
Mingozzi F, High KA. Immune responses to AAV vectors: overcoming barriers to successful gene therapy. Blood 2013;122:23-36. DOI: https://doi.org/10.1182/blood-2013-01-306647
Meliani A, Boisgerault F, Hardet R, et al. Antigen-selective modulation of AAV immunogenicity with tolerogenic rapamycin nanoparticles enables successful vector re-administration. Nat Commun 2018;9:4098. DOI: https://doi.org/10.1038/s41467-018-06621-3
Nathwani AC, Reiss U, Tuddenham E, et al. Adeno-associated mediated gene transfer for hemophilia B:8 year follow up and impact of removing "empty viral particles" on safety and efficacy of gene transfer. Blood 2018;132:491. DOI: https://doi.org/10.1182/blood-2018-99-118334
Louis Jeune V, Joergensen JA, Hajjar RJ, Weber T. Pre-existing anti-adeno-associated virus antibodies as a challenge in AAV gene therapy. Hum Gene Ther Methods 2013;24:59-67. DOI: https://doi.org/10.1089/hgtb.2012.243
McKay TR, Rahim AA, Buckley SM, et al. Perinatal gene transfer to the liver. Curr Pharm Design 2011;17:2528-41. DOI: https://doi.org/10.2174/138161211797247541
Coppoletta JM, Wolbach SB. Body length and organ weights of infants and children: a study of the body length and normal weights of the more important vital organs of the body between birth and twelve years of age. Am J Pathol 1933;9:55-70.
Chen H, Shi M, Gilam A, et al. Hemophilia A ameliorated in mice by CRISPR-based in vivo genome editing of human Factor VIII. Sci Rep 2019;9:16838. DOI: https://doi.org/10.1038/s41598-019-53198-y
Johnson V. First patient with hemophilia A dosed in new gene therapy trial. 2023 [cited 2023 December 29th]; Available from: https://www.cgtlive.com/view/first-patient-hemophilia-a-dosed-new-gene-therapy-trial
Mahlangu J, Kaczmarek R, von Drygalski A, et al. Two-year outcomes of valoctocogene roxaparvovec therapy for hemophilia A. N Engl J Med 2023;388:694-705. DOI: https://doi.org/10.1056/NEJMoa2211075
Cook K, Forbes SP, Adamski K, et al. Assessing the potential cost-effectiveness of a gene therapy for the treatment of hemophilia A. J Med Econ 2020;23:501-12. DOI: https://doi.org/10.1080/13696998.2020.1721508
Pipe S, Leebeek WG, Recht M, et al. Gene therapy with etranacogene dezaparvovec for hemophilia B. N Engl J Med 2023;388:706-18. DOI: https://doi.org/10.1056/NEJMoa2211644
Itzler R, Buckner TW, Leebeek FWG, et al. Effect of etranacogene dezaparvovec on quality of life for severe and moderately severe hemophilia B participants: results from the phase III HOPE-B trial 2 years after gene therapy. Hemophilia 2024;30:709-19. DOI: https://doi.org/10.1111/hae.14977
Quinn J, Delaney KA, Wong WY, et al. Psychometric validation of the Haemo-QOL-A in participants with hemophilia A treated with gene therapy. Patient Relat Outcome Meas 2022;13:169-80. DOI: https://doi.org/10.2147/PROM.S357555
Pasi KJ, Laffan M, Rangarajan S, et al. Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe hemophilia A. Hemophilia 2021;27:947-56. DOI: https://doi.org/10.1111/hae.14391
von Drygalski A, Gomez E, Giermasz A, et al. Stable and durable factor IX levels in patients with hemophilia B over 3 years after etranacogene dezaparvovec gene therapy. Blood Adv 2023;7:5671-9. DOI: https://doi.org/10.1182/bloodadvances.2022008886
Srivastava A, Santagostino E, Dougall A, et al. WFH Guidelines for the management of hemophilia, 3rd ed. Hemophilia 2020;26:1-158. DOI: https://doi.org/10.1111/hae.14046
Nathwani AC, Davidoff AM, Tuddenham EGD. Advances in gene therapy for hemophilia. Hum Gene Ther 2017;28:1004-12. DOI: https://doi.org/10.1089/hum.2017.167
Shah J, Kim H, Sivamurthy K, et al. Comprehensive analysis and prediction of long-term durability of factor IX activity following etranacogene dezaparvovec gene therapy in the treatment of hemophilia B. Curr Med Res Opin 2023;39:227-37. DOI: https://doi.org/10.1080/03007995.2022.2133492
Vokinger KN, Avorn J, Kesselheim AS. Sources of innovation in gene therapies - approaches to achieving affordable prices. N Engl J Med 2023;388:292-5. DOI: https://doi.org/10.1056/NEJMp2211729
Burke T, Asghar S, O'Hara J, et al. Clinical, humanistic, and economic burden of severe haemophilia B in adults receiving factor IX prophylaxis: findings from the CHESS II real-world burden of illness study in Europe. Orphanet J Rare Dis 2021;16:521. DOI: https://doi.org/10.1186/s13023-021-02152-1
Mancuso ME, Castaman G, Pochopien M, et al. Cost-minimization analysis of recombinant factor VIII Fc versus emicizumab for treating patients with hemophilia A without inhibitors in Europe. J Med Econ 2022;25:1068-75. DOI: https://doi.org/10.1080/13696998.2022.2115777
Jiang H, Pierce GF, Ozelo MC, et al. Evidence of multiyear factor IX expression by AAV-mediated gene transfer to skeletal muscle in an individual with severe hemophilia B. Mol Ther 2006;14:452-5. DOI: https://doi.org/10.1016/j.ymthe.2006.05.004
Spadarella G, Di Minno A, Milan G, et al. Paradigm shift for the treatment of hereditary hemophilia: towards precision medicine. Blood Rev 2020;39:100618. DOI: https://doi.org/10.1016/j.blre.2019.100618
Di Minno G, Tremoli E. Tailoring of medical treatment: hemostasis and thrombosis towards precision medicine. Haematologica 2017;102:411-8. DOI: https://doi.org/10.3324/haematol.2016.156000
Ponomarev AS, Chulpanova DS, Yanygina LM, et al. Emerging gene therapy approaches in the management of spinal muscular atrophy (SMA): an overview of clinical trials and patent landscape. Int J Mol Sci 2023;24. DOI: https://doi.org/10.3390/ijms241813743
Targeted Gene Insertion of Factor 9 as a Potential Durable Treatment for Hemophilia B. CRISPR/Cas9-mediated F9 gene insertion therapy / Intellia Therap, Regeneron - LARVOL DELTA 2023 [cited; Available from: https://delta.larvol.com/Products/?ProductId=234344ff-0ff4-493f-8c30-4f719fd027ae
Soni S. Gene therapies for transfusion dependent beta-thalassemia: current status and critical criteria for success. Am J Hematol 2020;95:1099-112. DOI: https://doi.org/10.1002/ajh.25909
Lambert C, Meite N, Sanogo I, et al. Hemophilia in Cote d'Ivoire (the Ivory Coast) in 2017: Extensive data collection as part of the World Federation of Hemophilia's twinning programme. Hemophilia 2019;25:236-43. DOI: https://doi.org/10.1111/hae.13682
Adair JE, Androski L, Bayigga L, et al. Towards access for all: 1st Working Group Report for the Global Gene Therapy Initiative (GGTI). Gene Ther 2023;30:216-21. DOI: https://doi.org/10.1038/s41434-021-00284-4
Aiuti A, Roncarolo MG, Naldini L. Gene therapy for ADA-SCID, the first marketing approval of an ex vivo gene therapy in Europe: paving the road for the next generation of advanced therapy medicinal products. EMBO Mol Med 2017;9:737-40. DOI: https://doi.org/10.15252/emmm.201707573
Thuret I, Ruggeri A, Angelucci E, Chabannon C. Hurdles to the adoption of gene therapy as a curative option for transfusion-dependent thalassemia. Stem Cells Translat Med 2022;11:407-14. DOI: https://doi.org/10.1093/stcltm/szac007
Migliavacca M, Barzaghi F, Fossati C, et al. Long-term and real-world safety and efficacy of retroviral gene therapy for adenosine deaminase deficiency. Nat Med 2024;30:488-97. DOI: https://doi.org/10.1038/s41591-023-02789-4
Gaudet D, Stroes ES, Méthot J, et al. Long-term retrospective analysis of gene therapy with alipogene tiparvovec and its effect on lipoprotein lipase deficiency-induced pancreatitis. Hum Gene Ther 2016;27:916-25. DOI: https://doi.org/10.1089/hum.2015.158
Maguire AM, High KA, Auricchio A, et al. Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial. Lancet 2009;374:1597-605. DOI: https://doi.org/10.1016/S0140-6736(09)61836-5
Maguire AM, Russell S, Chung DC, et al. Durability of Voretigene Neparvovec for Biallelic RPE65-mediated inherited retinal disease: phase 3 results at 3 and 4 years. Ophthalmology 2021;128:1460-8. DOI: https://doi.org/10.1016/j.ophtha.2021.03.031
Mendell JR, Al-Zaidy SA, Lehman KJ, et al. Five-Year Extension Results of the Phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy. JAMA Neurol 2021;78:834-41. DOI: https://doi.org/10.1001/jamaneurol.2021.1272
Retson L, Tiwari N, Vaughn J, et al. Epithelioid neoplasm of the spinal cord in a child with spinal muscular atrophy treated with onasemnogene abeparvovec. Mol Ther 2023;31:2991-8. DOI: https://doi.org/10.1016/j.ymthe.2023.08.013
Muhuri M, Levy DI, Schulz M, et al. Durability of transgene expression after rAAV gene therapy. Mol Ther 2022;30:1364-80. DOI: https://doi.org/10.1016/j.ymthe.2022.03.004
Meier N, Fuchs H, Galactionova K, et al. Cost-effectiveness analysis of etranacogene dezaparvovec versus extended half-life prophylaxis for moderate-to-severe haemophilia B in Germany. Pharmacoecon Open 2024;8:373-87. DOI: https://doi.org/10.1007/s41669-024-00480-z
Chapman M. German health insurance fund to reimburse Roctavian for hem A. 2023 Available from: https://hemophilianewstoday.com/news/german-health-insurance-fund-will-reimburse-rocatvian-hem-a/
Mannucci PM. Gene transfer in hemophilia A: not cogent yet. Bleed Thromb Vascul Biol 2022;1:32. DOI: https://doi.org/10.4081/btvb.2022.32
Castaman G. Gene transfer in hemophilia B: a big step forward. Bleed Thromb Vascul Biol 2023;2:70. DOI: https://doi.org/10.4081/btvb.2023.70
How to Cite
The evolving landscape of gene therapy for congenital severe hemophilia: a 2024 state of the art. (2024). Bleeding, Thrombosis and Vascular Biology, 3(2). https://doi.org/10.4081/btvb.2024.144
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