1932

Abstract

In vivo gene therapy is rapidly emerging as a new therapeutic paradigm for monogenic disorders. For almost three decades, hemophilia A (HA) and hemophilia B (HB) have served as model disorders for the development of gene therapy. This effort is soon to bear fruit with completed pivotal adeno-associated viral (AAV) vector gene addition trials reporting encouraging results and regulatory approval widely anticipated in the near future for the current generation of HA and HB AAV vectors. Here we review the clinical development of AAV gene therapy for HA and HB and examine outstanding questions that have recently emerged from AAV clinical trials for hemophilia and other monogenic disorders.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-med-043021-033013
2023-01-27
2024-06-25
Loading full text...

Full text loading...

/deliver/fulltext/med/74/1/annurev-med-043021-033013.html?itemId=/content/journals/10.1146/annurev-med-043021-033013&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Fassel H, McGuinn C. 2021. Haemophilia: factoring in new therapies. Br. J. Haematol. 194:5835–50
    [Google Scholar]
  2. 2.
    Birch CL. 1937. Hemophilia: Clinical and Genetic Aspects Champaign: Univ. Ill.
    [Google Scholar]
  3. 3.
    Skinner MW. 2012. WFH: closing the global gap—achieving optimal care. Haemophilia 18:41–12
    [Google Scholar]
  4. 4.
    Oldenburg J, Mahlangu JN, Kim B et al. 2017. Emicizumab prophylaxis in hemophilia A with inhibitors. N. Engl. J. Med. 377:9809–18
    [Google Scholar]
  5. 5.
    Mahlangu J, Oldenburg J, Paz-Priel I et al. 2018. Emicizumab prophylaxis in patients who have hemophilia A without inhibitors. N. Engl. J. Med. 379:9811–22
    [Google Scholar]
  6. 6.
    Mazepa MA, Monahan PE, Baker JR et al. 2016. Men with severe hemophilia in the United States: birth cohort analysis of a large national database. Blood 127:243073–81
    [Google Scholar]
  7. 7.
    Manco-Johnson MJ, Abshire TC, Shapiro AD et al. 2007. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N. Engl. J. Med. 357:6535–44
    [Google Scholar]
  8. 8.
    Nilsson I, Berntorp E, Löfqvist T, Pettersson H. 1992. Twenty-five years’ experience of prophylactic treatment in severe haemophilia A and B. J. Intern. Med. 232:125–32
    [Google Scholar]
  9. 9.
    Arruda VR, Doshi BS, Samelson-Jones BJ. 2017. Novel approaches to hemophilia therapy: successes and challenges. Blood 130:212251–56
    [Google Scholar]
  10. 10.
    Li C, Samulski RJ. 2020. Engineering adeno-associated virus vectors for gene therapy. Nat. Rev. Genet. 21:4255–72
    [Google Scholar]
  11. 11.
    Rumachik NG, Malaker SA, Poweleit N et al. 2020. Methods matter: standard production platforms for recombinant AAV produce chemically and functionally distinct vectors. Mol. Ther. Methods Clin. Dev. 18:98–118
    [Google Scholar]
  12. 12.
    Nowrouzi A, Penaud-Budloo M, Kaeppel C et al. 2012. Integration frequency and intermolecular recombination of rAAV vectors in non-human primate skeletal muscle and liver. Mol. Ther. 20:61177–86
    [Google Scholar]
  13. 13.
    Nguyen GN, Everett JK, Kafle S et al. 2021. A long-term study of AAV gene therapy in dogs with hemophilia A identifies clonal expansions of transduced liver cells. Nat. Biotechnol. 39:147–55
    [Google Scholar]
  14. 14.
    Wang D, Tai PWL, Gao G. 2019. Adeno-associated virus vector as a platform for gene therapy delivery. Nat. Rev. Drug. Discov. 18:5358–78
    [Google Scholar]
  15. 15.
    Okuyama T, Huber RM, Bowling W et al. 1996. Liver-directed gene therapy: a retroviral vector with a complete LTR and the ApoE enhancer-α 1-antitrypsin promoter dramatically increases expression of human α 1-antitrypsin in vivo. Hum. Gene Ther. 7:5637–45
    [Google Scholar]
  16. 16.
    Rettinger SD, Kennedy SC, Wu X et al. 1994. Liver-directed gene therapy: quantitative evaluation of promoter elements by using in vivo retroviral transduction. PNAS 91:41460–64
    [Google Scholar]
  17. 17.
    Costa RH, Grayson DR. 1991. Site-directed mutagenesis of hepatocyte nuclear factor (HNF) binding sites in the mouse transthyretin (TTR) promoter reveal synergistic interactions with its enhancer region. Nucleic Acids Res 19:154139–45
    [Google Scholar]
  18. 18.
    Brinkhous KM, Sandberg H, Garris JB et al. 1985. Purified human factor VIII procoagulant protein: comparative hemostatic response after infusions into hemophilic and von Willebrand disease dogs. PNAS 82:248752–56
    [Google Scholar]
  19. 19.
    Lind P, Larsson K, Spira J et al. 1995. Novel forms of B-domain deleted recombinant factor VIII molecules. Construction and biochemical characterization. Eur. J. Biochem. 232:19–27
    [Google Scholar]
  20. 20.
    Pittman DD, Alderman EM, Tomkinson KN et al. 1993. Biochemical, immunological, and in vivo functional characterization of B-domain-deleted FVIII. Blood 81:112925–35
    [Google Scholar]
  21. 21.
    McIntosh J, Lenting PJ, Rosales C et al. 2013. Therapeutic levels of FVIII following a single peripheral vein administration of rAAV vector encoding a novel human factor VIII variant. Blood 121:173335–44
    [Google Scholar]
  22. 22.
    Nathwani AC, Reiss UM, Tuddenham EG et al. 2014. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N. Engl. J. Med. 371:211994–2004
    [Google Scholar]
  23. 23.
    Nathwani AC, Tuddenham EG, Rangarajan S et al. 2011. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N. Engl. J. Med. 365:252357–65
    [Google Scholar]
  24. 24.
    Manno CS, Pierce GF, Arruda VR et al. 2006. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med 12:3342–47
    [Google Scholar]
  25. 25.
    Miesbach W, Meijer K, Coppens M et al. 2018. Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B. Blood 131:91022–31
    [Google Scholar]
  26. 26.
    Konkle BA, Walsh CE, Escobar MA et al. 2021. BAX 335 hemophilia B gene therapy clinical trial results: potential impact of CpG sequences on gene expression. Blood 137:6763–74
    [Google Scholar]
  27. 27.
    George LA, Sullivan SK, Giermasz A et al. 2017. Hemophilia B gene therapy with a high-specific-activity factor IX variant. N. Engl. J. Med. 377:232215–27
    [Google Scholar]
  28. 28.
    Von Drygalski A, Giermasz A, Castaman G et al. 2019. Etranacogene dezaparvovec (AMT-061 phase 2b): normal/near normal FIX activity and bleed cessation in hemophilia B. Blood Adv 3:213241–47
    [Google Scholar]
  29. 29.
    Simioni P, Tormene D, Tognin G et al. 2009. X-linked thrombophilia with a mutant factor IX (factor IX Padua). N. Engl. J. Med. 361:171671–75
    [Google Scholar]
  30. 30.
    Samelson-Jones BJ, Finn JD, George LA et al. 2019. Hyperactivity of factor IX Padua (R338L) depends on factor VIIIa cofactor activity. JCI Insight 4:14e128683
    [Google Scholar]
  31. 31.
    Shirley JL, de Jong YP, Terhorst C, Herzog RW. 2020. Immune responses to viral gene therapy vectors. Mol. Ther. 28:3709–22
    [Google Scholar]
  32. 32.
    Falese L, Sandza K, Yates B et al. 2017. Strategy to detect pre-existing immunity to AAV gene therapy. Gene Ther. 24:12768–78
    [Google Scholar]
  33. 33.
    Majowicz A, Nijmeijer B, Lampen MH et al. 2019. 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. 14:27–36
    [Google Scholar]
  34. 34.
    Klamroth R, Hayes G, Andreeva T et al. 2022. Global seroprevalence of pre-existing immunity against AAV5 and other AAV serotypes in people with hemophilia A. Hum. Gene Ther. 33:7–832–41
    [Google Scholar]
  35. 35.
    Calcedo R, Vandenberghe LH, Gao G et al. 2009. Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. J. Infect. Dis. 199:3381–90
    [Google Scholar]
  36. 36.
    Harrington EA, Sloan JL, Manoli I et al. 2016. Neutralizing antibodies against adeno-associated viral capsids in patients with mut methylmalonic acidemia. Hum. Gene Ther. 27:5345–53
    [Google Scholar]
  37. 37.
    George LA, Ragni MV, Rasko JEJ et al. 2020. Long-term follow-up of the first in human intravascular delivery of AAV for gene transfer: AAV2-hFIX16 for severe hemophilia B. Mol. Ther. 28:2073–82
    [Google Scholar]
  38. 38.
    Calcedo R, Wilson JM. 2016. AAV natural infection induces broad cross-neutralizing antibody responses to multiple AAV serotypes in chimpanzees. Hum. Gene Ther. Clin. Dev. 27:279–82
    [Google Scholar]
  39. 39.
    Aronson SJ, Veron P, Collaud F et al. 2019. Prevalence and relevance of pre-existing anti-adeno-associated virus immunity in the context of gene therapy for Crigler-Najjar syndrome. Hum. Gene Ther 30:101297–305
    [Google Scholar]
  40. 40.
    Wang L, Bell P, Somanathan S et al. 2015. Comparative study of liver gene transfer with AAV vectors based on natural and engineered AAV capsids. Mol. Ther. 23:121877–87
    [Google Scholar]
  41. 41.
    Mingozzi F, Chen Y, Murphy SL et al. 2012. Pharmacological modulation of humoral immunity in a nonhuman primate model of AAV gene transfer for hemophilia B. Mol. Ther. 20:71410–16
    [Google Scholar]
  42. 42.
    Pipe SW, Recht M, Key NS et al. 2020. First data from the phase 3 HOPE-B gene therapy trial: efficacy and safety of etranacogene dezaparvovec (AAV5-Padua hFIX variant; AMT-061) in adults with severe or moderate-severe hemophilia B treated irrespective of pre-existing anti-capsid neutralizing antibodies. Blood 136:LBA–6
    [Google Scholar]
  43. 43.
    Wang L, Calcedo R, Bell P et al. 2011. Impact of pre-existing immunity on gene transfer to nonhuman primate liver with adeno-associated virus 8 vectors. Hum. Gene Ther. 22:111389–401
    [Google Scholar]
  44. 44.
    Leborgne C, Barbon E, Alexander JM et al. 2020. IgG-cleaving endopeptidase enables in vivo gene therapy in the presence of anti-AAV neutralizing antibodies. Nat. Med. 26:71096–101
    [Google Scholar]
  45. 45.
    Majowicz A, Salas D, Zabaleta N et al. 2017. Successful repeated hepatic gene delivery in mice and non-human primates achieved by sequential administration of AAV5ch and AAV1. Mol. Ther. 25:81831–42
    [Google Scholar]
  46. 46.
    Paulk NK, Pekrun K, Zhu E et al. 2018. Bioengineered AAV capsids with combined high human liver transduction in vivo and unique humoral seroreactivity. Mol. Ther. 26:1289–303
    [Google Scholar]
  47. 47.
    Mullard A. 2021. Gene therapy community grapples with toxicity issues, as pipeline matures. Nat. Rev. Drug. Discov. 20:11804–5
    [Google Scholar]
  48. 48.
    Chand DH, Zaidman C, Arya K et al. 2021. Thrombotic microangiopathy following onasemnogene abeparvovec for spinal muscular atrophy: a case series. J. Pediatr. 231:265–68
    [Google Scholar]
  49. 49.
    Feldman AG, Parsons JA, Dutmer CM et al. 2020. Subacute liver failure following gene replacement therapy for spinal muscular atrophy type 1. J. Pediatr. 225:252–58
    [Google Scholar]
  50. 50.
    FDA Cellular, Tissue, and Gene Therapies Advisory Committee 2021. Toxicity risks of adeno-associated virus (AAV) vectors for gene therapy (GT) Briefing doc., CTGTAC Meet. 70. https://www.fda.gov/media/151599/download
    [Google Scholar]
  51. 51.
    Rocket Pharm 2021. Rocket Pharmaceuticals announces positive updates from phase 1 clinical trial of RP-A501 in Danon disease News release, Nov. 15. https://ir.rocketpharma.com/news-releases/news-release-details/rocket-pharmaceuticals-announces-positive-updates-phase-1
    [Google Scholar]
  52. 52.
    Guillou J, de Pellegars A, Porcheret F et al. 2022. Fatal thrombotic microangiopathy case following adeno-associated viral SMN gene therapy. Blood Adv. 6:4266–70
    [Google Scholar]
  53. 53.
    Hordeaux J, Buza EL, Dyer C et al. 2020. Adeno-associated virus-induced dorsal root ganglion pathology. Hum. Gene Ther 31:15–16808–18
    [Google Scholar]
  54. 54.
    Hordeaux J, Buza EL, Jeffrey B et al. 2020. MicroRNA-mediated inhibition of transgene expression reduces dorsal root ganglion toxicity by AAV vectors in primates. Sci. Transl. Med. 12:569aba9188
    [Google Scholar]
  55. 55.
    Mueller C, Berry JD, McKenna-Yasek DM et al. 2020. SOD1 suppression with adeno-associated virus and microRNA in familial ALS. N. Engl. J. Med. 383:2151–58
    [Google Scholar]
  56. 56.
    George LA, Monahan PE, Eyster ME et al. 2021. Multiyear factor VIII expression after AAV gene transfer for hemophilia A. N. Engl. J. Med. 385:211961–73
    [Google Scholar]
  57. 57.
    Pasi KJ, Rangarajan S, Mitchell N et al. 2020. Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for hemophilia A. N. Engl. J. Med. 382:129–40
    [Google Scholar]
  58. 58.
    Ozelo MC, Mahlangu J, Pasi KJ et al. 2022. Valoctocogene roxaparvovec gene therapy for hemophilia A. N. Engl. J. Med. 386:111013–25
    [Google Scholar]
  59. 59.
    Chowdary P, Shapiro S, Makris M et al. 2020. A novel adeno associated virus (AAV) gene therapy (FLT180a) achieves normal FIX activity levels in severe hemophilia B (HB) patients (B-AMAZE Study). Res. Pract. Thromb. Haemost. 4:Suppl. 217
    [Google Scholar]
  60. 60.
    Visweshwar N, Harrington TJ, Leavitt AD et al. 2021. Updated results of the Alta Study, a phase 1/2 study of giroctocogene fitelparvovec (PF-07055480/SB-525) gene therapy in adults with severe hemophilia A. Blood 138:564
    [Google Scholar]
  61. 61.
    Rangarajan S, Walsh L, Lester W et al. 2017. AAV5-factor VIII gene transfer in severe hemophilia A. N. Engl. J. Med. 377:262519–30
    [Google Scholar]
  62. 62.
    Mingozzi F, Maus MV, Hui DJ et al. 2007. CD8+ T-cell responses to adeno-associated virus capsid in humans. Nat. Med. 13:4419–22
    [Google Scholar]
  63. 63.
    FDA 2021. Highlights of prescribing information, Zolgensma 2019. https://www.fda.gov/media/126109/download
  64. 64.
    Shieh PB, Bonnemann CG, Muller-Felber W et al. 2020. Re: “Moving forward after two deaths in a gene therapy trial of myotubular myopathy” by Wilson and Flotte. Hum. Gene Ther. 31:15–16787
    [Google Scholar]
  65. 65.
    Neese JM, Yum S, Matesanz S et al. 2021. Intracranial hemorrhage secondary to vitamin K deficiency in X-linked myotubular myopathy. Neuromuscul. Disord. 31:7651–55
    [Google Scholar]
  66. 66.
    Nault JC, Datta S, Imbeaud S et al. 2015. Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas. Nat. Genet. 47:101187–93
    [Google Scholar]
  67. 67.
    Chandler RJ, LaFave MC, Varshney GK et al. 2015. Vector design influences hepatic genotoxicity after adeno-associated virus gene therapy. J. Clin. Investig. 125:2870–80
    [Google Scholar]
  68. 68.
    Nakai H, Montini E, Fuess S et al. 2003. AAV serotype 2 vectors preferentially integrate into active genes in mice. Nat. Genet. 34:3297–302
    [Google Scholar]
  69. 69.
    Donsante A, Miller DG, Li Y et al. 2007. AAV vector integration sites in mouse hepatocellular carcinoma. Science 317:5837477
    [Google Scholar]
  70. 70.
    Schmidt MRFG, Coppens M, Thomsen H et al. 2021. Liver safety case report from the phase 3 HOPE-B gene therapy trial in adults with hemophilia B. Res. Pract. . Thromb. Haemost. 5:Suppl. 2OC 67.4 (Abstr.)
    [Google Scholar]
  71. 71.
    Koster T, Blann AD, Briet E et al. 1995. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 345:8943152–55
    [Google Scholar]
  72. 72.
    Kyrle PA, Minar E, Hirschl M et al. 2000. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N. Engl. J. Med. 343:7457–62
    [Google Scholar]
  73. 73.
    Rietveld IM, Lijfering WM, le Cessie S et al. 2019. High levels of coagulation factors and venous thrombosis risk: strongest association for factor VIII and von Willebrand factor. J. Thromb. Haemost. 17:199–109
    [Google Scholar]
  74. 74.
    Pfizer 2021. Pfizer and Sangamo announce updated phase 1/2 results showing sustained bleeding control in highest dose cohort through two years following hemophilia A gene therapy Presss Release, Dec. 14. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-sangamo-announce-updated-phase-12-results-1
    [Google Scholar]
  75. 75.
    Crudele JM, Finn JD, Siner JI et al. 2015. AAV liver expression of FIX-Padua prevents and eradicates FIX inhibitor without increasing thrombogenicity in hemophilia B dogs and mice. Blood 125:101553–61
    [Google Scholar]
  76. 76.
    Finn JD, Ozelo MC, Sabatino DE et al. 2010. Eradication of neutralizing antibodies to factor VIII in canine hemophilia A after liver gene therapy. Blood 116:265842–48
    [Google Scholar]
  77. 77.
    Mingozzi F, Hasbrouck NC, Basner-Tschakarjan E et al. 2007. Modulation of tolerance to the transgene product in a nonhuman primate model of AAV-mediated gene transfer to liver. Blood 110:72334–41
    [Google Scholar]
  78. 78.
    Samelson-Jones BJ, Arruda VR. 2020. Translational potential of immune tolerance induction by AAV liver-directed factor VIII gene therapy hemophilia A. Front. Immunol. 11:618
    [Google Scholar]
  79. 79.
    Ragni MV, George LA. 2019. The national blueprint for future factor VIII inhibitor clinical trials: NHLBI State of the Science (SOS) Workshop on factor VIII inhibitors. Haemophilia 25:4581–89
    [Google Scholar]
  80. 80.
    Ferriere S, Peyron I, Christophe OD et al. 2020. A hemophilia A mouse model for the in vivo assessment of emicizumab function. Blood 136:6740–48
    [Google Scholar]
  81. 81.
    Zou C, Vercauteren KOA, Michailidis E et al. 2020. Experimental variables that affect human hepatocyte AAV transduction in liver chimeric mice. Mol. Ther. Methods Clin. Dev. 18:189–98
    [Google Scholar]
  82. 82.
    Sternberg AR, Davidson RJ, Samelson-Jones BJ, George L. 2021. In vitro and in vivo models to understand one-stage and chromogenic factor VIII activity assay discrepancy of hepatocyte-derived factor VIII. Res. Pract. Thromb. Haemost. 5:Suppl. 1OC 75.3 (Abstr.)
    [Google Scholar]
  83. 83.
    Robinson MM, George LA, Carr ME et al. 2021. Factor IX assay discrepancies in the setting of liver gene therapy using a hyperfunctional variant factor IX-Padua. J. Thromb. Haemost. 19:51212–18
    [Google Scholar]
  84. 84.
    Niemeyer GP, Herzog RW, Mount J et al. 2009. Long-term correction of inhibitor-prone hemophilia B dogs treated with liver-directed AAV2-mediated factor IX gene therapy. Blood 113:4797–806
    [Google Scholar]
  85. 85.
    Nathwani AC, Reiss U, Tuddenham E et al. 2019. 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 132:Suppl. 1491
    [Google Scholar]
  86. 86.
    Ozelo MC, Mahlangu J, Pasi K et al. 2021. Efficacy and safety of valoctocogene roxaparvovec adeno-associated virus gene transfer for severe hemophilia A: results from the phase 3 GENEr8-1 trial. Res. Pract. Thromb. Haemost. 5(Suppl. 2): Abstr.
    [Google Scholar]
  87. 87.
    BioMarin Pharm 2022. BioMarin announces stable and durable annualized bleed control in the largest phase 3 gene therapy study in adults with severe hemophilia A; 134-participant study met all primary and secondary efficacy endpoints at two year analysis News Release, Jan. 9. https://investors.biomarin.com/2022-01-09-BioMarin-Announces-Stable-and-Durable-Annualized-Bleed-Control-in-the-Largest-Phase-3-Gene-Therapy-Study-in-Adults-with-Severe-Hemophilia-A-134-Participant-Study-Met-All-Primary-and-Secondary-Efficacy-Endpoints-at-Two-Year-Analysis
    [Google Scholar]
  88. 88.
    Pasi KJ, Rangarajan S, Robinson TM et al. 2021. Hemostatic response is maintained for up to 5 years following treatment with valoctocogene roxaparvovec, an AAV5-hFVIII-SQ gene therapy for severe hemophilia A. Res. Pract. Thromb Haemost. 5:Suppl. 2OC 67.1 (Abstr.)
    [Google Scholar]
  89. 89.
    George LA. 2021. Hemophilia gene therapy: ushering in a new treatment paradigm?. Hematol. Am. Soc. Hematol. Educ. Progr. 2021:1226–33
    [Google Scholar]
  90. 90.
    Lange AM, Altynova ES, Nguyen GN, Sabatino DE. 2016. Overexpression of factor VIII after AAV delivery is transiently associated with cellular stress in hemophilia A mice. Mol. Ther. Methods Clin. Dev. 3:16064
    [Google Scholar]
  91. 91.
    Zolotukhin I, Markusic DM, Palaschak B et al. 2016. Potential for cellular stress response to hepatic factor VIII expression from AAV vector. Mol. Ther. Methods Clin. Dev. 3:16063
    [Google Scholar]
  92. 92.
    Poothong J, Pottekat A, Siirin M et al. 2020. Factor VIII exhibits chaperone-dependent and glucose-regulated reversible amyloid formation in the endoplasmic reticulum. Blood 135:211899–911
    [Google Scholar]
  93. 93.
    Fong S, Yates B, Sihn CR et al. 2022. Interindividual variability in transgene mRNA and protein production following adeno-associated virus gene therapy for hemophilia A. Nat. Med. 28:4789–97
    [Google Scholar]
  94. 94.
    Huang H-R, Moroski-Erkul C, Bialek P et al. 2019. CRISPR/Cas9-mediated targeted insertion of human F9 achieves therapeutic circulating protein levels in mice and non-human primates. Mol. Ther. 27:4 Suppl. 17 (Abstr.)
    [Google Scholar]
  95. 95.
    Samelson-Jones BJ, Arruda VR. 2019. Protein-engineered coagulation factors for hemophilia gene therapy. Mol. Ther. Methods Clin. Dev. 12:184–201
    [Google Scholar]
  96. 96.
    Wilhelm AR, Parsons NA, Samelson-Jones BJ et al. 2021. Activated protein C has a regulatory role in factor VIII function. Blood 137:182532–43
    [Google Scholar]
  97. 97.
    Du LM, Nurden P, Nurden AT et al. 2013. Platelet-targeted gene therapy with human factor VIII establishes haemostasis in dogs with haemophilia A. Nat. Commun. 4:2773
    [Google Scholar]
  98. 98.
    Shi Q, Wilcox DA, Fahs SA et al. 2006. Factor VIII ectopically targeted to platelets is therapeutic in hemophilia A with high-titer inhibitory antibodies. J. Clin. Investig. 116:71974–82
    [Google Scholar]
  99. 99.
    Greene TK, Wang C, Hirsch JD et al. 2010. In vivo efficacy of platelet-delivered, high specific activity factor VIII variants. Blood 116:266114–22
    [Google Scholar]
  100. 100.
    Follenzi A, Benten D, Novikoff P et al. 2008. Transplanted endothelial cells repopulate the liver endothelium and correct the phenotype of hemophilia A mice. J. Clin. Investig. 118:3935–45
    [Google Scholar]
  101. 101.
    Pipe SW, Leebeek FW, Recht M et al. 2021. 52 Week efficacy and safety of etranacogene dezaparvovec in adults with severe or moderate-severe hemophilia B: data from the phase 3 HOPE-B gene therapy trial. Res. Pract. Thromb. Haemost. 5:Suppl. 2 PB0653 (Abstr.)
    [Google Scholar]
  102. 102.
    Pipe SW, Hay CRM, Sheehan J et al. 2020. First-in-human gene therapy study of AAVhu37 capsid vector technology in severe hemophilia A: safety and FVIII activity results. Res. Pract. Thromb. Haemost. 4:Suppl. 1OC 09.4 (Abstr.)
    [Google Scholar]
  103. 103.
    uniQure 2021. uniQure and CSL Behring announce primary endpoint achieved in HOPE-B pivotal trial of etranacogene dezaparvovec gene therapy in patients with hemophilia B News Release, Dec. 9. https://www.globenewswire.com/news-release/2021/12/09/2349067/0/en/uniQure-and-CSL-Behring-Announce-Primary-Endpoint-Achieved-in-HOPE-B-Pivotal-Trial-of-Etranacogene-Dezaparvovec-Gene-Therapy-in-Patients-with-Hemophilia-B.html
    [Google Scholar]
  104. 104.
    Rosen S, Tiefenbacher S, Robinson M et al. 2020. Activity of transgene-produced B-domain-deleted factor VIII in human plasma following AAV5 gene therapy. Blood 136:222524–34
    [Google Scholar]
/content/journals/10.1146/annurev-med-043021-033013
Loading
/content/journals/10.1146/annurev-med-043021-033013
Loading

Data & Media loading...

Supplementary Data

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error