Gene Therapy for Hemophilia: Progress to Date

BioDrugs

Volumn 32, Issue 1, 2018, Pages 9-25

  Chapin, John C ^a   Monahan, Paul Edward ^a  

^a SHIRE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BLOOD CLOTTING FACTOR 8; BLOOD CLOTTING FACTOR 9; NEUTRALIZING ANTIBODY; TOLL LIKE RECEPTOR;

ARTICLE; CARCINOGENESIS; CLINICAL TRIAL; CYTOTOXIC T LYMPHOCYTE; HEMOPHILIA; HEMOPHILIA B; HEPATITIS; HUMAN; IMMUNE RESPONSE; NONHUMAN; PRIORITY JOURNAL; VIRAL GENE THERAPY; VIRUS PARTICLE; DEPENDOPARVOVIRUS; GENE THERAPY; GENETICS; HEMOPHILIA A; IMMUNOLOGY; PROCEDURES;

DEPENDOVIRUS; GENETIC THERAPY; HEMOPHILIA A; HEMOPHILIA B; HUMANS;

EID: 85033446057     PISSN: 11738804     EISSN: 1179190X     Source Type: Journal    
DOI: 10.1007/s40259-017-0255-0     Document Type: Article

References (159)

1. Wong T, Recht M. Current options and new developments in the treatment of haemophilia. Drugs. 2011;71(3):305–20.
2. den Uijl IE, Fischer K, Van Der Bom JG, Grobbee DE, Rosendaal FR, Plug I. Analysis of low frequency bleeding data: the association of joint bleeds according to baseline FVIII activity levels. Haemophilia. 2011;17(1):41–4.
3. Den Uijl IE, Mauser Bunschoten EP, Roosendaal G, Schutgens RE, Biesma DH, Grobbee DE, et al. Clinical severity of haemophilia A: does the classification of the 1950s still stand? Haemophilia. 2011;17(6):849–53.
4. Löfqvist T, Nilsson IM, Berntorp E, Pettersson H. Haemophilia prophylaxis in young patients—a long-term follow-up. J Intern Med. 1997;241(5):395–400.
5. Mazepa MA, Monahan PE, Baker JR, Riske BK, Soucie JM, Network UHTC. Men with severe hemophilia in the United States: birth cohort analysis of a large national database. Blood. 2016;127(24):3073–81.
6. Darby SC, Kan SW, Spooner RJ, Giangrande PL, Hill FG, Hay CR, et al. Mortality rates, life expectancy, and causes of death in people with hemophilia A or B in the United Kingdom who were not infected with HIV. Blood. 2007;110(3):815–25.
7. Oladapo AO, Epstein JD, Williams E, Ito D, Gringeri A, Valentino LA. Health-related quality of life assessment in haemophilia patients on prophylaxis therapy: a systematic review of results from prospective clinical trials. Haemophilia. 2015;21(5):e344–58.
8. 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. N Engl J Med. 2007;357(6):535–44.
9. 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 Syst Rev. 2011;(9):CD003429.
10. Stonebraker JS, Brooker M, Amand RE, Farrugia A, Srivastava A. A study of reported factor VIII use around the world. Haemophilia. 2010;16(1):33–46.
11. Stonebraker JS, Bolton-Maggs PH, Brooker M, Farrugia A, Srivastava A. A study of reported factor IX use around the world. Haemophilia. 2011;17(3):446–55.
12. 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. N Engl J Med. 2013;369(24):2313–23.
13. Mahlangu J, Powell JS, Ragni MV, Chowdary P, Josephson NC, Pabinger I, et al. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood. 2014;123(3):317–25.
14. 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.
15. Oldenburg J, Mahlangu JN, Kim B, Schmitt C, Callaghan MU, Young G, et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med. 2017;377(9):809–18.
16. Pasi KJ, Rangarajan S, Georgiev P, Mant T, Creagh MD, Lissitchkov T, et al. Targeting of antithrombin in hemophilia A or B with RNAi therapy. N Engl J Med. 2017;377(9):819–28.
17. Gouw SC, van der Bom JG, Marijke van den Berg H. Treatment-related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL cohort study. Blood. 2007;109(11):4648–54.
18. DiMichele D. Inhibitor development in haemophilia B: an orphan disease in need of attention. Br J Haematol. 2007;138(3):305–15.
19. Anson DS, Hock RA, Austen D, Smith KJ, Brownlee GG, Verma IM, et al. Towards gene therapy for hemophilia B. Mol Biol Med. 1987;4(1):11–20.
20. 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.
21. Xu L, Nichols TC, Sarkar R, McCorquodale S, Bellinger DA, Ponder KP. Absence of a desmopressin response after therapeutic expression of factor VIII in hemophilia A dogs with liver-directed neonatal gene therapy. Proc Natl Acad Sci USA. 2005;102(17):6080–5.
22. Kay MA, Rothenberg S, Landen CN, Bellinger DA, Leland F, Toman C, et al. In vivo gene therapy of hemophilia B: sustained partial correction in factor IX-deficient dogs. Science. 1993;262(5130):117–9.
23. 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. Proc Natl Acad Sci USA. 1999;96(18):10379–84.
24. Greengard JS, Jolly DJ. Animal testing of retroviral-mediated gene therapy for factor VIII deficiency. Thromb Haemost. 1999;82(2):555–61.
25. Powell JS, Ragni MV, White GC, 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.
26. Mátrai J, Chuah MK, VandenDriessche T. Recent advances in lentiviral vector development and applications. Mol Ther. 2010;18(3):477–90.
27. Cantore A, Ranzani M, Bartholomae CC, Volpin M, Valle PD, Sanvito F, et al. Liver-directed lentiviral gene therapy in a dog model of hemophilia B. Sci Transl Med. 2015;7(277):277ra28.
28. Suwanmanee T, Hu G, Gui T, Bartholomae CC, Kutschera I, von Kalle C, et al. Integration-deficient lentiviral vectors expressing codon-optimized R338L human FIX restore normal hemostasis in Hemophilia B mice. Mol Ther. 2014;22(3):567–74.
29. Matsui H, Hegadorn C, Ozelo M, Burnett E, Tuttle A, Labelle A, et al. A microRNA-regulated and GP64-pseudotyped lentiviral vector mediates stable expression of FVIII in a murine model of Hemophilia A. Mol Ther. 2011;19(4):723–30.
30. Kuether EL, Schroeder JA, Fahs SA, Cooley BC, Chen Y, Montgomery RR, et al. Lentivirus-mediated platelet gene therapy of murine hemophilia A with pre-existing anti-factor VIII immunity. J Thromb Haemost. 2012;10(8):1570–80.
31. Cavazzana-Calvo M, Lagresle C, Hacein-Bey-Abina S, Fischer A. Gene therapy for severe combined immunodeficiency. Annu Rev Med. 2005;56:585–602.
32. Schmidt M, Hacein-Bey-Abina S, Wissler M, Carlier F, Lim A, Prinz C, et al. Clonal evidence for the transduction of CD34+ cells with lymphomyeloid differentiation potential and self-renewal capacity in the SCID-X1 gene therapy trial. Blood. 2005;105(7):2699–706.
33. Hacein-Bey-Abina S, von Kalle C, Schmidt M, Le Deist F, Wulffraat N, McIntyre E, et al. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med. 2003;348(3):255–6.
34. Miao CH, Ohashi K, Patijn GA, Meuse L, Ye X, Thompson AR, et al. Inclusion of the hepatic locus control region, an intron, and untranslated region increases and stabilizes hepatic factor IX gene expression in vivo but not in vitro. Mol Ther. 2000;1(6):522–32.
35. Yant SR, Meuse L, Chiu W, Ivics Z, Izsvak Z, Kay MA. Somatic integration and long-term transgene expression in normal and haemophilic mice using a DNA transposon system. Nat Genet. 2000;25(1):35–41.
36. Olivares EC, Hollis RP, Chalberg TW, Meuse L, Kay MA, Calos MP. Site-specific genomic integration produces therapeutic factor IX levels in mice. Nat Biotechnol. 2002;20(11):1124–8.
37. Lin Y, Chang L, Solovey A, Healey JF, Lollar P, Hebbel RP. Use of blood outgrowth endothelial cells for gene therapy for hemophilia A. Blood. 2002;99(2):457–62.
38. Roth DA, Tawa NE, O’Brien JM, Treco DA, Selden RF. Group FVTTS. Nonviral transfer of the gene encoding coagulation factor VIII in patients with severe hemophilia A. N Engl J Med. 2001;344(23):1735–42.
39. Atchinson RW, Casto BC, Hammon WM. Adenovirus-associated defective virus particles. Science. 1965;149(3685):754–6.
40. Melnick JL, Mayor HD, Smith KO, Rapp F. Association of 20-millimicron particles with adenoviruses. J Bacteriol. 1965;90(1):271–4.
41. Xie Q, Bu W, Bhatia S, Hare J, Somasundaram T, Azzi A, et al. The atomic structure of adeno-associated virus (AAV-2), a vector for human gene therapy. Proc Natl Acad Sci USA. 2002;99(16):10405–10.
42. Schnepp BC, Jensen RL, Clark KR, Johnson PR. Infectious molecular clones of adeno-associated virus isolated directly from human tissues. J Virol. 2009;83(3):1456–64.
43. Kotin RM, Siniscalco M, Samulski RJ, Zhu XD, Hunter L, Laughlin CA, et al. Site-specific integration by adeno-associated virus. Proc Natl Acad Sci USA. 1990;87(6):2211–5.
44. Afione SA, Conrad CK, Kearns WG, Chunduru S, Adams R, Reynolds TC, et al. In vivo model of adeno-associated virus vector persistence and rescue. J Virol. 1996;70(5):3235–41.
45. Schnepp BC, Jensen RL, Chen CL, Johnson PR, Clark KR. Characterization of adeno-associated virus genomes isolated from human tissues. J Virol. 2005;79(23):14793–803.
46. Gissen P, Arias IM. Structural and functional hepatocyte polarity and liver disease. J Hepatol. 2015;63(4):1023–37.
47. Gruppuso PA, Sanders JA. Regulation of liver development: implications for liver biology across the lifespan. J Mol Endocrinol. 2016;56(3):R115–25.
48. Jacobs F, Gordts SC, Muthuramu I, De Geest B. The liver as a target organ for gene therapy: state of the art, challenges, and future perspectives. Pharmaceuticals (Basel). 2012;5(12):1372–92.
49. Gao G, Vandenberghe LH, Alvira MR, Lu Y, Calcedo R, Zhou X, et al. Clades of adeno-associated viruses are widely disseminated in human tissues. J Virol. 2004;78(12):6381–8.
50. Nathwani AC, Cochrane M, McIntosh J, Ng CY, Zhou J, Gray JT, et al. Enhancing transduction of the liver by adeno-associated viral vectors. Gene Ther. 2009;16(1):60–9.
51. Gao GP, Alvira MR, Wang L, Calcedo R, Johnston J, Wilson JM. Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. Proc Natl Acad Sci USA. 2002;99(18):11854–9.
52. Zincarelli C, Soltys S, Rengo G, Rabinowitz JE. Analysis of AAV serotypes 1–9 mediated gene expression and tropism in mice after systemic injection. Mol Ther. 2008;16(6):1073–80.
53. Wang L, Wang H, Bell P, McCarter RJ, He J, Calcedo R, et al. Systematic evaluation of AAV vectors for liver directed gene transfer in murine models. Mol Ther. 2010;18(1):118–25.
54. Monahan PE, Samulski RJ, Tazelaar J, Xiao X, Nichols TC, Bellinger DA, et al. Direct intramuscular injection with recombinant AAV vectors results in sustained expression in a dog model of hemophilia. Gene Ther. 1998;5(1):40–9.
55. Chao H, Samulski R, Bellinger D, Monahan P, Nichols T, Walsh C. Persistent expression of canine factor IX in hemophilia B canines. Gene Ther. 1999;6(10):1695–704.
56. Scallan CD, Lillicrap D, Jiang H, Qian X, Patarroyo-White SL, Parker AE, et al. Sustained phenotypic correction of canine hemophilia A using an adeno-associated viral vector. Blood. 2003;102(6):2031–7.
57. Snyder RO, Miao CH, Patijn GA, Spratt SK, Danos O, Nagy D, et al. Persistent and therapeutic concentrations of human factor IX in mice after hepatic gene transfer of recombinant AAV vectors. Nat Genet. 1997;16(3):270–6.
58. Snyder RO, Miao C, Meuse L, Tubb J, Donahue BA, Lin HF, et al. Correction of hemophilia B in canine and murine models using recombinant adeno-associated viral vectors. Nat Med. 1999;5(1):64–70.
59. Wang L, Takabe K, Bidlingmaier SM, Ill CR, Verma IM. Sustained correction of bleeding disorder in hemophilia B mice by gene therapy. Proc Natl Acad Sci USA. 1999;96(7):3906–10.
60. Wang L, Nichols TC, Read MS, Bellinger DA, Verma IM. Sustained expression of therapeutic level of factor IX in hemophilia B dogs by AAV-mediated gene therapy in liver. Mol Ther. 2000;1(2):154–8.
61. Nathwani AC, Davidoff AM, Hanawa H, Hu Y, Hoffer FA, Nikanorov A, et al. Sustained high-level expression of human factor IX (hFIX) after liver-targeted delivery of recombinant adeno-associated virus encoding the hFIX gene in rhesus macaques. Blood. 2002;100(5):1662–9.
62. Kessler PD, Podsakoff GM, Chen X, McQuiston SA, Colosi PC, Matelis LA, et al. Gene delivery to skeletal muscle results in sustained expression and systemic delivery of a therapeutic protein. Proc Natl Acad Sci USA. 1996;93(24):14082–7.
63. Hauck B, Zhao W, High K, Xiao W. Intracellular viral processing, not single-stranded DNA accumulation, is crucial for recombinant adeno-associated virus transduction. J Virol. 2004;78(24):13678–86.
64. Fisher KJ, Jooss K, Alston J, Yang Y, Haecker SE, High K, et al. Recombinant adeno-associated virus for muscle directed gene therapy. Nat Med. 1997;3(3):306–12.
65. Herzog RW, Fields PA, Arruda VR, Brubaker JO, Armstrong E, McClintock D, et al. Influence of vector dose on factor IX-specific T and B cell responses in muscle-directed gene therapy. Hum Gene Ther. 2002;13(11):1281–91.
66. Fields PA, Arruda VR, Armstrong E, Chu K, Mingozzi F, Hagstrom JN, et al. Risk and prevention of anti-factor IX formation in AAV-mediated gene transfer in the context of a large deletion of F9. Mol Ther. 2001;4(3):201–10.
67. Kay MA, Manno CS, Ragni MV, Larson PJ, Couto LB, McClelland A, et al. Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector. Nat Genet. 2000;24(3):257–61.
68. 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.
69. Wang L, Cao O, Swalm B, Dobrzynski E, Mingozzi F, Herzog RW. Major role of local immune responses in antibody formation to factor IX in AAV gene transfer. Gene Ther. 2005;12(19):1453–64.
70. Herzog RW, Yang EY, Couto LB, Hagstrom JN, Elwell D, Fields PA, et al. Long-term correction of canine hemophilia B by gene transfer of blood coagulation factor IX mediated by adeno-associated viral vector. Nat Med. 1999;5(1):56–63.
71. Herzog RW, Mount JD, Arruda VR, High KA, Lothrop CD. Muscle-directed gene transfer and transient immune suppression result in sustained partial correction of canine hemophilia B caused by a null mutation. Mol Ther. 2001;4(3):192–200.
72. Buchlis G, Podsakoff GM, Radu A, Hawk SM, Flake AW, Mingozzi F, et al. Factor IX expression in skeletal muscle of a severe hemophilia B patient 10 years after AAV-mediated gene transfer. Blood. 2012;119(13):3038–41.
73. Mount JD, Herzog RW, Tillson DM, Goodman SA, Robinson N, McCleland ML, 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.
74. 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. Nat Med. 2006;12(3):342–7.
75. Nathwani AC, Tuddenham EG, Rangarajan S, Rosales C, McIntosh J, Linch DC, et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med. 2011;365(25):2357–65.
76. 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. N Engl J Med. 2014;371(21):1994–2004.
77. Simioni P, Tormene D, Tognin G, Gavasso S, Bulato C, Iacobelli NP, et al. X-linked thrombophilia with a mutant factor IX (factor IX Padua). N Engl J Med. 2009;361(17):1671–5.
78. Samelson-Jones B, Finn J, Camire R, Arruda V. New hyperactive Factor IX variants bioengineered based upon biochemical studies of Factor IX Padua. Blood. 2016;128(22):1384.
79. Finn JD, Nichols TC, Svoronos N, Merricks EP, Bellenger DA, Zhou S, 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(23):4521–3.
80. Monahan PE, Sun J, Gui T, Hu G, Hannah WB, Wichlan DG, et al. Employing a gain-of-function factor IX variant R338L to advance the efficacy and safety of hemophilia B human gene therapy: preclinical evaluation supporting an ongoing adeno-associated virus clinical trial. Hum Gene Ther. 2015;26(2):69–81.
81. Monahan P, Walsh C, Powell J, Konkle B, Josephson N, Escobar M, et al. Update on a phase 1/2 open-label trial of BAX335, an adeno-associated virus 8 (AAV8) vector-based gene therapy program for hemophilia B. J Thromb Haemost. 2015;13(Suppl. 2):1–997.
82. Herzog RW. Hemophilia gene therapy: caught between a cure and an immune response. Mol Ther. 2015;23(9):1411–2.
83. George L, Giermasz A, Sullivan S, Ducore J, Rasko J, Samelson-Jones B, et al. SPK-9001: adeno-associated virus mediated gene transfer for haemophilia B achieved durable endogenous prophylaxis at levels of activity sufficient to achieve significant mean reduction in annual bleeding and infusions rates in preliminary data from an on-going phase 1/2a trial. Res Pract Thromb Haemost. 2017;1:1–1451.
84. Lind P, Larsson K, Spira J, Sydow-Bäckman M, Almstedt A, Gray E, et al. Novel forms of B-domain-deleted recombinant factor VIII molecules. Construction and biochemical characterization. Eur J Biochem. 1995;232(1):19–27.
85. Pasi J, Wong W, Rangarajan S, Wilde J, Perry D, Madan B, et al. Interim results of an open-label, phase 1/2 study of BMN 270, an AAV5-FVIII gene transfer in severe hemophilia A. Haemophilia. 2016;22(S4):151–2.
86. Zolotukhin I, Markusic DM, Palaschak B, Hoffman BE, Srikanthan MA, Herzog RW. Potential for cellular stress response to hepatic factor VIII expression from AAV vector. Mol Ther Methods Clin Dev. 2016;3:16063.
87. Pillay S, Meyer NL, Puschnik AS, Davulcu O, Diep J, Ishikawa Y, et al. An essential receptor for adeno-associated virus infection. Nature. 2016;530(7588):108–12.
88. Murphy SL, Li H, Zhou S, Schlachterman A, High K. Prolonged susceptibility to antibody-mediated neutralization for adeno-associated vectors targeted to the liver. Mol Ther. 2008;16(1):138–45.
89. Halbert CL, Standaert TA, Wilson CB, Miller AD. Successful readministration of adeno-associated virus vectors to the mouse lung requires transient immunosuppression during the initial exposure. J Virol. 1998;72(12):9795–805.
90. Jiang H, Couto LB, Patarroyo-White S, Liu T, Nagy D, Vargas JA, et al. Effects of transient immunosuppression on adenoassociated, virus-mediated, liver-directed gene transfer in rhesus macaques and implications for human gene therapy. Blood. 2006;108(10):3321–8.
91. Wang L, Calcedo R, Bell P, Lin J, Grant RL, Siegel DL, et al. Impact of pre-existing immunity on gene transfer to nonhuman primate liver with adeno-associated virus 8 vectors. Hum Gene Ther. 2011;22(11):1389–401.
92. Li C, Narkbunnam N, Samulski RJ, Asokan A, Hu G, Jacobson LJ, et al. Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia. Gene Ther. 2012;19(3):288–94.
93. 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(11):1990–7.
94. Stilwell JL, Samulski RJ. Adeno-associated virus vectors for therapeutic gene transfer. Biotechniques. 2003;34(1):148–50, 52, 54 passim.
95. Ferrari FK, Samulski T, Shenk T, Samulski RJ. Second-strand synthesis is a rate-limiting step for efficient transduction by recombinant adeno-associated virus vectors. J Virol. 1996;70(5):3227–34.
96. Li C, He Y, Nicolson S, Hirsch M, Weinberg MS, Zhang P, et al. Adeno-associated virus capsid antigen presentation is dependent on endosomal escape. J Clin Investig. 2013;123(3):1390–401.
97. Monahan PE, Lothrop CD, Sun J, Hirsch ML, Kafri T, Kantor B, et al. Proteasome inhibitors enhance gene delivery by AAV virus vectors expressing large genomes in hemophilia mouse and dog models: a strategy for broad clinical application. Mol Ther. 2010;18(11):1907–16.
98. Wu Z, Sun J, Zhang T, Yin C, Yin F, Van Dyke T, et al. Optimization of self-complementary AAV vectors for liver-directed expression results in sustained correction of hemophilia B at low vector dose. Mol Ther. 2008;16(2):280–9.
99. McCarty DM, Monahan PE, Samulski RJ. Self-complementary recombinant adeno-associated virus (scAAV) vectors promote efficient transduction independently of DNA synthesis. Gene Ther. 2001;8(16):1248–54.
100. 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.
101. Wu J, Zhao W, Zhong L, Han Z, Li B, Ma W, et al. Self-complementary recombinant adeno-associated viral vectors: packaging capacity and the role of rep proteins in vector purity. Hum Gene Ther. 2007;18(2):171–82.
102. Dominguez E, Marais T, Chatauret N, Benkhelifa-Ziyyat S, Duque S, Ravassard P, et al. Intravenous scAAV9 delivery of a codon-optimized SMN1 sequence rescues SMA mice. Hum Mol Genet. 2011;20(4):681–93.
103. Foster H, Sharp PS, Athanasopoulos T, Trollet C, Graham IR, Foster K, et al. Codon and mRNA sequence optimization of microdystrophin transgenes improves expression and physiological outcome in dystrophic mdx mice following AAV2/8 gene transfer. Mol Ther. 2008;16(11):1825–32.
104. Wang L, Morizono H, Lin J, Bell P, Jones D, McMenamin D, et al. Preclinical evaluation of a clinical candidate AAV8 vector for ornithine transcarbamylase (OTC) deficiency reveals functional enzyme from each persisting vector genome. Mol Genet Metab. 2012;105(2):203–11.
105. Ward NJ, Buckley SM, Waddington SN, Vandendriessche T, Chuah MK, Nathwani AC, et al. Codon optimization of human factor VIII cDNAs leads to high-level expression. Blood. 2011;117(3):798–807.
106. Shestopal SA, Hao JJ, Karnaukhova E, Liang Y, Ovanesov MV, Lin M, et al. Expression and characterization of a codon-optimized blood coagulation factor VIII. J Thromb Haemost. 2017;15(4):709–20.
107. Kimchi-Sarfaty C, Schiller T, Hamasaki-Katagiri N, Khan MA, Yanover C, Sauna ZE. Building better drugs: developing and regulating engineered therapeutic proteins. Trends Pharmacol Sci. 2013;34(10):534–48.
108. Kuriyama S, Yoshikawa M, Ishizaka S, Tsujii T, Ikenaka K, Kagawa T, et al. A potential approach for gene therapy targeting hepatoma using a liver-specific promoter on a retroviral vector. Cell Struct Funct. 1991;16(6):503–10.
109. Schiedner G, Morral N, Parks RJ, Wu Y, Koopmans SC, Langston C, et al. Genomic DNA transfer with a high-capacity adenovirus vector results in improved in vivo gene expression and decreased toxicity. Nat Genet. 1998;18(2):180–3.
110. Nair N, Rincon MY, Evens H, Sarcar S, Dastidar S, Samara-Kuko E, et al. Computationally designed liver-specific transcriptional modules and hyperactive factor IX improve hepatic gene therapy. Blood. 2014;123(20):3195–9.
111. Falkner F, Horling F, Lengler J, Weiller M, Mayrhofer J, Turecek M, et al. Development of a lead candidate for Shire’s AAV8-based FVIII gene therapy program BAX 888. Haemophilia. 2016;22(S4):1–152.
112. Wright JF. Manufacturing and characterizing AAV-based vectors for use in clinical studies. Gene Ther. 2008;15(11):840–8.
113. Sommer JM, Smith PH, Parthasarathy S, Isaacs J, Vijay S, Kieran J, et al. Quantification of adeno-associated virus particles and empty capsids by optical density measurement. Mol Ther. 2003;7(1):122–8.
114. Allay JA, Sleep S, Long S, Tillman DM, Clark R, Carney G, et al. Good manufacturing practice production of self-complementary serotype 8 adeno-associated viral vector for a hemophilia B clinical trial. Hum Gene Ther. 2011;22(5):595–604.
115. Mingozzi F, Anguela XM, Pavani G, Chen Y, Davidson RJ, Hui DJ, et al. Overcoming preexisting humoral immunity to AAV using capsid decoys. Sci Transl Med. 2013;5(194):194ra92.
116. Gao K, Li M, Zhong L, Su Q, Li J, Li S, et al. Empty virions in AAV8 vector preparations reduce transduction efficiency and may cause total viral particle dose-limiting side-effects. Mol Ther Methods Clin Dev. 2014;1(9):20139.
117. Pien GC, Basner-Tschakarjan E, Hui DJ, Mentlik AN, Finn JD, Hasbrouck NC, et al. Capsid antigen presentation flags human hepatocytes for destruction after transduction by adeno-associated viral vectors. J Clin Investig. 2009;119(6):1688–95.
118. Gruntman AM, Su L, Su Q, Gao G, Mueller C, Flotte TR. Stability and compatibility of recombinant adeno-associated virus under conditions commonly encountered in human gene therapy trials. Hum Gene Ther Methods. 2015;26(2):71–6.
119. Mingozzi F, High KA. Therapeutic in vivo gene transfer for genetic disease using AAV: progress and challenges. Nat Rev Genet. 2011;12(5):341–55.
120. Li H, Murphy SL, Giles-Davis W, Edmonson S, Xiang Z, Li Y, et al. Pre-existing AAV capsid-specific CD8+ T cells are unable to eliminate AAV-transduced hepatocytes. Mol Ther. 2007;15(4):792–800.
121. Li C, Hirsch M, Asokan A, Zeithaml B, Ma H, Kafri T, et al. Adeno-associated virus type 2 (AAV2) capsid-specific cytotoxic T lymphocytes eliminate only vector-transduced cells coexpressing the AAV2 capsid in vivo. J Virol. 2007;81(14):7540–7.
122. Wang L, Figueredo J, Calcedo R, Lin J, Wilson JM. Cross-presentation of adeno-associated virus serotype 2 capsids activates cytotoxic T cells but does not render hepatocytes effective cytolytic targets. Hum Gene Ther. 2007;18(3):185–94.
123. Siders WM, Shields J, Kaplan J, Lukason M, Woodworth L, Wadsworth S, et al. Cytotoxic T lymphocyte responses to transgene product, not adeno-associated viral capsid protein, limit transgene expression in mice. Hum Gene Ther. 2009;20(1):11–20.
124. Palaschak B, Marsic D, Herzog RW, Zolotukhin S, Markusic DM. An immune-competent murine model to study elimination of AAV-transduced hepatocytes by capsid-specific CD8(+) T cells. Mol Ther Methods Clin Dev. 2017;5:142–52.
125. Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001;2(8):675–80.
126. Gallucci S, Matzinger P. Danger signals: SOS to the immune system. Curr Opin Immunol. 2001;13(1):114–9.
127. Mosaheb MM, Reiser ML, Wetzler LM. Toll-like receptor ligand-based vaccine adjuvants require intact MyD88 signaling in antigen-presenting cells for germinal center formation and antibody production. Front Immunol. 2017;8:225.
128. Somanathan S, Breous E, Bell P, Wilson JM. AAV vectors avoid inflammatory signals necessary to render transduced hepatocyte targets for destructive T cells. Mol Ther. 2010;18(5):977–82.
129. Zhu J, Huang X, Yang Y. The TLR9-MyD88 pathway is critical for adaptive immune responses to adeno-associated virus gene therapy vectors in mice. J Clin Investig. 2009;119(8):2388–98.
130. Wu TL, Li H, Faust SM, Chi E, Zhou S, Wright F, et al. CD8+ T cell recognition of epitopes within the capsid of adeno-associated virus 8-based gene transfer vectors depends on vectors’ genome. Mol Ther. 2014;22(1):42–51.
131. Faust SM, Bell P, Cutler BJ, Ashley SN, Zhu Y, Rabinowitz JE, et al. CpG-depleted adeno-associated virus vectors evade immune detection. J Clin Investig. 2013;123(7):2994–3001.
132. Veron P, Leborgne C, Monteilhet V, Boutin S, Martin S, Moullier P, et al. Humoral and cellular capsid-specific immune responses to adeno-associated virus type 1 in randomized healthy donors. J Immunol. 2012;188(12):6418–24.
133. Parzych EM, Li H, Yin X, Liu Q, Wu TL, Podsakoff GM, et al. Effects of immunosuppression on circulating adeno-associated virus capsid-specific T cells in humans. Hum Gene Ther. 2013;24(4):431–42.
134. Sabatino DE, Mingozzi F, Hui DJ, Chen H, Colosi P, Ertl HC, et al. Identification of mouse AAV capsid-specific CD8+ T cell epitopes. Mol Ther. 2005;12(6):1023–33.
135. Hui DJ, Edmonson SC, Podsakoff GM, Pien GC, Ivanciu L, Camire RM, et al. AAV capsid CD8+ T-cell epitopes are highly conserved across AAV serotypes. Mol Ther Methods Clin Dev. 2015;2:15029.
136. Li H, Lasaro MO, Jia B, Lin SW, Haut LH, High KA, et al. Capsid-specific T-cell responses to natural infections with adeno-associated viruses in humans differ from those of nonhuman primates. Mol Ther. 2011;19(11):2021–30.
137. Mingozzi F, Maus MV, Hui DJ, Sabatino DE, Murphy SL, Rasko JE, et al. CD8(+) T-cell responses to adeno-associated virus capsid in humans. Nat Med. 2007;13(4):419–22.
138. Crudele JM, Finn JD, Siner JI, Martin NB, Niemeyer GP, Zhou S, 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(10):1553–61.
139. Mingozzi F, Liu YL, Dobrzynski E, Kaufhold A, Liu JH, Wang Y, et al. Induction of immune tolerance to coagulation factor IX antigen by in vivo hepatic gene transfer. J Clin Investig. 2003;111(9):1347–56.
140. Ziegler RJ, Cherry M, Barbon CM, Li C, Bercury SD, Armentano D, et al. Correction of the biochemical and functional deficits in Fabry mice following AAV8-mediated hepatic expression of α-galactosidase A. Mol Ther. 2007;15(3):492–500.
141. Sun B, Kulis MD, Young SP, Hobeika AC, Li S, Bird A, et al. Immunomodulatory gene therapy prevents antibody formation and lethal hypersensitivity reactions in murine Pompe disease. Mol Ther. 2010;18(2):353–60.
142. Mingozzi F, Hasbrouck NC, Basner-Tschakarjan E, Edmonson SA, Hui DJ, Sabatino DE, et al. Modulation of tolerance to the transgene product in a nonhuman primate model of AAV-mediated gene transfer to liver. Blood. 2007;110(7):2334–41.
143. Cooper M, Nayak S, Hoffman BE, Terhorst C, Cao O, Herzog RW. Improved induction of immune tolerance to factor IX by hepatic AAV-8 gene transfer. Hum Gene Ther. 2009;20(7):767–76.
144. Breous E, Somanathan S, Vandenberghe LH, Wilson JM. Hepatic regulatory T cells and Kupffer cells are crucial mediators of systemic T cell tolerance to antigens targeting murine liver. Hepatology. 2009;50(2):612–21.
145. Nakai H, Yant SR, Storm TA, Fuess S, Meuse L, Kay MA. Extrachromosomal recombinant adeno-associated virus vector genomes are primarily responsible for stable liver transduction in vivo. J Virol. 2001;75(15):6969–76.
146. Miao CH, Snyder RO, Schowalter DB, Patijn GA, Donahue B, Winther B, et al. The kinetics of rAAV integration in the liver. Nat Genet. 1998;19(1):13–5.
147. Nakai H, Montini E, Fuess S, Storm TA, Grompe M, Kay MA. AAV serotype 2 vectors preferentially integrate into active genes in mice. Nat Genet. 2003;34(3):297–302.
148. Donsante A, Vogler C, Muzyczka N, Crawford JM, Barker J, Flotte T, et al. Observed incidence of tumorigenesis in long-term rodent studies of rAAV vectors. Gene Ther. 2001;8(17):1343–6.
149. Donsante A, Miller DG, Li Y, Vogler C, Brunt EM, Russell DW, et al. AAV vector integration sites in mouse hepatocellular carcinoma. Science. 2007;317(5837):477.
150. Zhong L, Malani N, Li M, Brady T, Xie J, Bell P, et al. Recombinant adeno-associated virus integration sites in murine liver after ornithine transcarbamylase gene correction. Hum Gene Ther. 2013;24(5):520–5.
151. Chandler RJ, LaFave MC, Varshney GK, Trivedi NS, Carrillo-Carrasco N, Senac JS, et al. Vector design influences hepatic genotoxicity after adeno-associated virus gene therapy. J Clin Investig. 2015;125(2):870–80.
152. Bell P, Wang L, Lebherz C, Flieder DB, Bove MS, Wu D, et al. No evidence for tumorigenesis of AAV vectors in a large-scale study in mice. Mol Ther. 2005;12(2):299–306.
153. Li H, Malani N, Hamilton SR, Schlachterman A, Bussadori G, Edmonson SE, et al. Assessing the potential for AAV vector genotoxicity in a murine model. Blood. 2011;117(12):3311–9.
154. Nault JC, Datta S, Imbeaud S, Franconi A, Mallet M, Couchy G, et al. Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas. Nat Genet. 2015;47(10):1187–93.
155. Büning H, Schmidt M. Adeno-associated vector toxicity-to be or not to be? Mol Ther. 2015;23(11):1673–5.
156. Nault JC, Mami I, La Bella T, Datta S, Imbeaud S, Franconi A, et al. Wild-type AAV insertions in hepatocellular carcinoma do not inform debate over genotoxicity risk of vectorized AAV. Mol Ther. 2016;24(4):660–1.
157. Boutin S, Monteilhet V, Veron P, Leborgne C, Benveniste O, Montus MF, 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(6):704–12.
158. Lu DR, Zhou JM, Zheng B, Qiu XF, Xue JL, Wang JM, et al. Stage I clinical trial of gene therapy for hemophilia B. Sci China B. 1993;36(11):1342–51.
159. Zhang WW, Josephs SF, Zhou J, Fang X, Alemany R, Balagué C, et al. Development and application of a minimal-adenoviral vector system for gene therapy of hemophilia A. Thromb Haemost. 1999;82(2):562–71.