Unraveling the Complex Story of Immune Responses to AAV Vectors Trial After Trial

Human Gene Therapy

Volumn 28, Issue 11, 2017, Pages 1061-1074

  Vandamme, Céline ^a,b,e   Adjali, Oumeya ^b,f   Mingozzi, Federico ^c,d  

^a UNIVERSITY OF EASTERN FINLAND   (Finland)

^b UNIVERSITÉ DE NANTES   (France)

^c Genethon and IMSERM U951 ^*  (France)

^d SORBONNE UNIVERSITÉ   (France)

^e Faculty of Health Sciences   (Finland)

^f UNIVERSITÉ DE NANTES   (France)

Author keywords

AAV vectors; antibody responses; gene therapy; immune responses; T cells

Indexed keywords

ADENO ASSOCIATED VIRUS VECTOR; ANTIVIRUS AGENT; NEUTRALIZING ANTIBODY; CAPSID PROTEIN;

ADAPTIVE IMMUNITY; ANTIVIRAL ACTIVITY; CELLULAR IMMUNITY; CLINICAL TRIAL (TOPIC); DONOR; HUMAN; HUMORAL IMMUNITY; IMMUNE RESPONSE; IMMUNOGENICITY; IMMUNOREACTIVITY; INNATE IMMUNITY; NONHUMAN; PRECLINICAL STUDY; PREVALENCE; REVIEW; T LYMPHOCYTE; TRANSGENE; VIRUS CAPSID; VIRUS NEUTRALIZATION; CD8+ T LYMPHOCYTE; DEPENDOPARVOVIRUS; GENE THERAPY; GENE VECTOR; GENETICS; IMMUNOLOGY; THERAPEUTIC USE; TRENDS;

CAPSID PROTEINS; CD8-POSITIVE T-LYMPHOCYTES; CLINICAL TRIALS AS TOPIC; DEPENDOVIRUS; GENETIC THERAPY; GENETIC VECTORS; HUMANS; IMMUNITY, CELLULAR;

EID: 85031674493     PISSN: 10430342     EISSN: 15577422     Source Type: Journal    
DOI: 10.1089/hum.2017.150     Document Type: Review

References (136)

1. Bainbridge JWB, Mehat MS, Sundaram V, et al. Long-term effect of gene therapy on Leber's congenital amaurosis. N Engl J Med 2015;372: 1887-1897.
2. Maguire AM, High KA, Auricchio A, et al. Agedependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a Phase 1 doseescalation trial. Lancet 2009;374:1597-1605.
3. Nathwani AC, Reiss UM, Tuddenham EGD, et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med 2014;371: 1994-2004.
4. Mueller C, Chulay JD, Trapnell BC, et al. Human Treg responses allow sustained recombinant adeno-associated virus-mediated transgene expression. J Clin Invest 2013;123:5310-5318.
5. Mueller C, Gernoux G, Gruntman AM, et al. 5 Year expression and neutrophil defect repair after gene therapy in alpha-1 antitrypsin deficiency. Mol Ther 2017;25:1387-1394.
6. Carpentier AC, Frisch F, Labbé SM, et al. Effect of alipogene tiparvovec (AAV1-LPLS447X) on postprandial chylomicron metabolism in lipoprotein lipase-deficient patients. J Clin Endocrinol Metab 2012;97:1635-1644.
7. Burnett JR, Hooper AJ. Alipogene tiparvovec, an adeno-associated virus encoding the Ser(447)X variant of the human lipoprotein lipase gene for the treatment of patients with lipoprotein lipase deficiency. Curr Opin Mol Ther 2009;11:681-691.
8. Gao G, Vandenberghe LH, Alvira MR, et al. Clades of adeno-associated viruses are widely disseminated in human tissues. J Virol 2004;78:6381-6388.
9. Berns KI, Muzyczka N. AAV: an overview of unanswered questions. Hum Gene Ther 2017;28: 308-313.
10. Blacklow NR, Hoggan MD, Kapikian AZ, et al. Epidemiology of adenovirus-associated virus infection in a nursery population. Am J Epidemiol 1968;88:368-378.
11. Blacklow NR, Hoggan MD, Rowe WP. Serologic evidence for human infection with adenovirusassociated viruses. J Natl Cancer Inst 1968;40: 319-327.
12. Basner-Tschakarjan E, Mingozzi F. Cell-mediated immunity to AAV vectors, evolving concepts and potential solutions. Front Immunol 2014;5.
13. Tse LV, Moller-Tank S, Asokan A. Strategies to circumvent humoral immunity to adeno-associated viral vectors. Expert Opin Biol Ther 2015;15: 845-855.
14. Trinchieri G, Sher A. Cooperation of Toll-like receptor signals in innate immune defence. Nat Rev Immunol 2007;7:179-190.
15. Abbas AK, Lichtman AH. Basic Immunology: Functions and Disorders of the Immune System. 3rd ed. Philadelphia, PA: Saunders/Elsevier, 2010.
16. 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;21:704-712.
17. Calcedo R, Vandenberghe LH, Gao G, et al. Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. J Infect Dis 2009;199:381-390.
18. Calcedo R, Morizono H, Wang L, et al. Adenoassociated virus antibody profiles in newborns, children, and adolescents. Clin Vaccine Immunol 2011;18:1586-1588.
19. Calcedo R, Wilson JM. Humoral immune response to AAV. Front Immunol 2013;4.
20. Halbert CL, Miller AD, McNamara S, et al. Prevalence of neutralizing antibodies against adenoassociated virus (AAV) types 2, 5, and 6 in cystic fibrosis and normal populations: implications for gene therapy using AAV vectors. Hum Gene Ther 2006;17:440-447.
21. Mingozzi F, Chen Y, Edmonson SC, et al. Prevalence and pharmacological modulation of humoral immunity to AAV vectors in gene transfer to synovial tissue. Gene Ther 2013;20:417-424.
22. Veron P, Leborgne C, Monteilhet V, et al. Humoral and cellular capsid-specific immune responses to adeno-associated virus type 1 in randomized healthy donors. J Immunol 2012;188: 6418-6424.
23. Thwaite R, Pagès G, Chillón M, et al. AAVrh.10 immunogenicity in mice and humans. Relevance of antibody cross-reactivity in human gene therapy. Gene Ther 2015;22:196-201.
24. Parks WP, Boucher DW, Melnick JL, et al. Seroepidemiological and ecological studies of the adenovirus-associated satellite viruses. Infect Immun 1970;2:716-722.
25. Chirmule N, Propert K, Magosin S, et al. Immune responses to adenovirus and adeno-associated virus in humans. Gene Ther 1999;6:1574-1583.
26. Wagner JA, Nepomuceno IB, Messner AH, et al. A Phase II, double-blind, randomized, placebocontrolled clinical trial of tgAAVCF using maxillary sinus delivery in patients with cystic fibrosis with antrostomies. Hum Gene Ther 2002;13: 1349-1359.
27. Moss RB, Rodman D, Spencer LT, et al. Repeated adeno-associated virus serotype 2 aerosolmediated cystic fibrosis transmembrane regulator gene transfer to the lungs of patients with cystic fibrosis: a multicenter, double-blind, placebocontrolled trial. Chest 2004;125:509-521.
28. Murphy SL, Li H, Mingozzi F, et al. Diverse IgG subclass responses to adeno-associated virus infection and vector administration. J Med Virol 2009;81:65-74.
29. Corden A, Handelman B, Yin H, et al. Neutralizing antibodies against adeno-associated viruses in Sjögren's patients: implications for gene therapy. Gene Ther 2017;24:241-244.
30. Ferla R, Claudiani P, Savarese M, et al. Prevalence of anti-adeno-associated virus serotype 8 neutralizing antibodies and arylsulfatase B cross-reactive immunologic material in mucopolysaccharidosis VI patient candidates for a gene therapy trial. Hum Gene Ther 2015;26:145-152.
31. Li C, Narkbunnam N, Samulski RJ, et al. Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia. Gene Ther 2012;19:288-294.
32. Mingozzi F, High KA. Immune responses to AAV vectors: overcoming barriers to successful gene therapy. Blood 2013;122:23-36.
33. Calcedo R, Wilson JM. AAV natural infection induces broad cross-neutralizing antibody responses to multiple AAV serotypes in chimpanzees. Hum Gene Ther Clin Dev 2016;27:79-82.
34. Wang L, Calcedo R, Bell P, et al. Impact of preexisting immunity on gene transfer to nonhuman primate liver with adeno-associated virus 8 vectors. Hum Gene Ther 2011;22:1389-1401.
35. Fitzpatrick Z, Leborgne C, Barbon E, et al. Influence of pre-existing anti-capsid neutralizing and binding antibodies on AAV-mediated liver transduction. ASGCT abstract. 2017.
36. Erles K, Sebökovà P, Schlehofer JR. Update on the prevalence of serum antibodies (IgG and IgM) to adeno-associated virus (AAV). J Med Virol 1999; 59:406-411.
37. Hurlbut GD, Ziegler RJ, Nietupski JB, et al. Preexisting immunity and low expression in primates highlight translational challenges for liverdirected AAV8-mediated gene therapy. Mol Ther J Am Soc Gene Ther 2010;18:1983-1994.
38. Jeune VL, Joergensen JA, Hajjar RJ, et al. Preexisting anti-adeno-associated virus antibodies as a challenge in AAV gene therapy. Hum Gene Ther Methods 2013;24:59-67.
39. Mingozzi F, Meulenberg JJ, Hui DJ, et al. AAV-1-mediated gene transfer to skeletal muscle in humans results in dose-dependent activation of capsid-specific T cells. Blood 2009;114:2077-2086.
40. Manno CS, Glenn F. Pierce, 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;12:342-347.
41. Mingozzi F, Maus MV, Hui DJ, et al. CD8+ T-cell responses to adeno-associated virus capsid in humans. Nat Med 2007;13:419-422.
42. Li H, Lasaro MO, Jia B, et al. Capsid-specific Tcell responses to natural infections with adenoassociated viruses in humans differ from those of nonhuman primates. Mol Ther 2011;19:2021-2030.
43. Hui DJ, Edmonson SC, Podsakoff GM, et al. AAV capsid CD8+ T-cell epitopes are highly conserved across AAV serotypes. Mol Ther Methods Clin Dev 2015;2:15029.
44. Murphy SL, Li H, Zhou S, et al. Prolonged susceptibility to antibody-mediated neutralization for adeno-associated vectors targeted to the liver. Mol Ther 2008;16:138-145.
45. Scallan CD, Jiang H, Liu T, et al. Human immunoglobulin inhibits liver transduction by AAV vectors at low AAV2 neutralizing titers in SCID mice. Blood 2006;107:1810-1817.
46. Jiang H, Couto LB, Patarroyo-White S, 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;108:3321-3328.
47. Cottard V, Valvason C, Falgarone G, et al. Immune response against gene therapy vectors: influence of synovial fluid on adeno-associated virus mediated gene transfer to chondrocytes. J Clin Immunol 2004;24:162-169.
48. Arruda VR, Stedman HH, Haurigot V, et al. Peripheral transvenular delivery of adeno-associated viral vectors to skeletal muscle as a novel therapy for hemophilia B. Blood 2010;115:4678-4688.
49. Rodino-Klapac LR, Montgomery CL, Mendell JR, et al. AAV-mediated gene therapy to the isolated limb in rhesus macaques. Methods Mol Biol 2011; 709:287-298.
50. Hajjar RJ, Zsebo K, Deckelbaum L, et al. Design of a Phase 1/2 trial of intracoronary administration of AAV1/SERCA2a in patients with heart failure. J Card Fail 2008;14:355-367.
51. Bennett J, Ashtari M, Wellman J, et al. AAV2 gene therapy readministration in three adults with congenital blindness. Sci Transl Med 2012;4: 120ra15-120ra15.
52. Kaplitt MG, Feigin A, Tang C, et al. Safety and tolerability of gene therapy with an adenoassociated virus (AAV) borne GAD gene for Parkinson's disease: an open label, Phase I trial. Lancet 2007;369:2097-2105.
53. Samaranch L, Salegio EA, San Sebastian W, et al. Adeno-associated virus serotype 9 transduction in the central nervous system of nonhuman primates. Hum Gene Ther 2012;23:382-389.
54. Chirmule N, Xiao W, Truneh A, et al. Humoral immunity to adeno-associated virus type 2 vectors following administration to murine and nonhuman primate muscle. J Virol 2000;74:2420-2425.
55. Haurigot V, Mingozzi F, Buchlis G, et al. Safety of AAV Factor IX peripheral transvenular gene delivery to muscle in hemophilia B dogs. Mol Ther 2010;18:1318-1329.
56. Nathwani AC, Gray JT, McIntosh J, et al. Safe and efficient transduction of the liver after peripheral vein infusion of self-complementary AAV vector results in stable therapeutic expression of human FIX in nonhuman primates. Blood 2007;109:1414-1421.
57. Flotte TR, Trapnell BC, Humphries M, et al. Phase 2 clinical trial of a recombinant adeno-associated viral vector expressing α1-antitrypsin: interim results. Hum Gene Ther 2011;22:1239-1247.
58. Nathwani AC, Tuddenham EGD, Rangarajan S, et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med 2011;365:2357-2365.
59. Amado D, Mingozzi F, Hui D, et al. Safety and efficacy of subretinal readministration of a viral vector in large animals to treat congenital blindness. Sci Transl Med 2010;2:21ra16.
60. 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;119:3038-3041.
61. Bortolussi G, Zentillin L, Vaníkova J, et al. Lifelong correction of hyperbilirubinemia with a neonatal liver-specific AAV-mediated gene transfer in a lethal mouse model of Crigler-Najjar syndrome. Hum Gene Ther 2014;25:844-855.
62. Ronzitti G, Bortolussi G, van Dijk R, et al. A translationally optimized AAV-UGT1A1 vector drives safe and long-lasting correction of Crigler-Najjar syndrome. Mol Ther Methods Clin Dev 2016;3:16049.
63. Wang L, Bell P, Lin J, et al. AAV8-mediated hepatic gene transfer in infant rhesus monkeys (Macaca mulatta). Mol Ther 2011;19:2012-2020.
64. Mount JD, Herzog RW, Tillson DM, et al. Sustained phenotypic correction of hemophilia B dogs with a factor IX null mutation by liver-directed gene therapy. Blood 2002;99:2670-2676.
65. Boisgérault F, Mingozzi F. The skeletal muscle environment and its role in immunity and tolerance to AAV vector-mediated gene transfer. Curr Gene Ther 2015;15:381-394.
66. Brantly ML, Chulay JD, Wang L, et al. Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy. Proc Natl Acad Sci U S A 2009;106: 16363-16368.
67. Ferreira V, Petry H, Salmon F. Immune responses to AAV-vectors, the Glybera example from bench to bedside. Front Immunol 2014;5.
68. Mendell JR, Rodino-Klapac LR, Rosales XQ, et al. Sustained alpha-sarcoglycan gene expression following gene transfer in LGMD2D. Ann Neurol 2010;68:629-638.
69. Gernoux G, Wilson JM, Mueller C. Regulatory and exhausted t cell responses to AAV capsid. Hum Gene Ther 2017;28:338-349.
70. Le Guiner C, Servais L, Montus M, et al. Longterm microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy. Nat Commun 2017;8:16105.
71. Mak KY, Rajapaksha IG, Angus PW, et al. The adeno-associated virus-a safe and effective vehicle for liver-specific gene therapy of inherited and non-inherited diseases. Curr Gene Ther 2017; 17:4-16.
72. Flotte TR, Mueller C. What is suppression of anti-adeno-associated virus capsid T-cells achieving? Hum Gene Ther 2014;25:178-179.
73. Arruda VR, Favaro P, Finn JD. Strategies to modulate immune responses: a new frontier for gene therapy. Mol Ther J Am Soc Gene Ther 2009; 17:1492-1503.
74. Mingozzi F, Hasbrouck NC, Basner-Tschakarjan E, et al. Modulation of tolerance to the transgene product in a nonhuman primate model of AAVmediated gene transfer to liver. Blood 2007;110: 2334-2341.
75. Stieger K, Schroeder J, Provost N, et al. Detection of intact rAAV particles up to 6 years after successful gene transfer in the retina of dogs and primates. Mol Ther 2009;17:516-523.
76. Pien GC, Basner-Tschakarjan E, Hui DJ, et al. Capsid antigen presentation flags human hepatocytes for destruction after transduction by adeno-associated viral vectors. J Clin Invest 2009; 119:1688-1695.
77. Finn JD, Hui DJ, Downey H, et al. Proteasome inhibitors decrease AAV2 capsid derived peptide epitope presentation on MHC class I following transduction. Mol Ther 2010;18:135-142.
78. Kishimoto TK, Ferrari JD, LaMothe RA, et al. Improving the efficacy and safety of biologic drugs with tolerogenic nanoparticles. Nat Nanotechnol 2016;11:890-899.
79. Meliani A, Boisgerault F, Marmier S, et al. Modulation of AAV vector dosing and avoidance of capsid immune responses via repeated coadministration of vector with tolerogenic rapamycin nanoparticles. Res Pract Thromb Haemost 2017;1:1-1451.
80. Gao G, Wang Q, Calcedo R, et al. Adeno-associated virus-mediated gene transfer to nonhuman primate liver can elicit destructive transgene-specific T cell responses. Hum Gene Ther 2009;20:930-942.
81. Guidotti LG, Iannacone M. Effector CD8 T cell trafficking within the liver. Mol Immunol 2013;55: 94-99.
82. Lang KS, Georgiev P, Recher M, et al. Immunoprivileged status of the liver is controlled by Toll-like receptor 3 signaling. J Clin Invest 2006; 116:2456-2463.
83. Nguyen DH, Hurtado-Ziola N, Gagneux P, et al. Loss of Siglec expression on T lymphocytes during human evolution. Proc Natl Acad Sci U S A 2006;103:7765-7770.
84. Eastwood D, Findlay L, Poole S, et al. Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4+ effector memory T-cells. Br J Pharmacol 2010;161: 512-526.
85. Poirier N, Mary C, Le Bas-Bernardet S, et al. Advantages of Papio anubis for preclinical testing of immunotoxicity of candidate therapeutic antagonist antibodies targeting CD28. MAbs 2014;6: 697-706.
86. Porter CM, Horvath-Arcidiacono JA, Singh AK, et al. Characterization and expansion of baboon CD4+CD25+ Treg cells for potential use in a non-human primate xenotransplantation model. Xenotransplantation 2007;14:298-308.
87. McTiernan CF, Mathier MA, Zhu X, et al. Myocarditis following adeno-associated viral gene expression of human soluble TNF receptor (TNFRII-Fc) in baboon hearts. Gene Ther 2007;14:1613-1622.
88. Song S, Scott-Jorgensen M, Wang J, et al. Intramuscular administration of recombinant adeno-associated virus 2 α-1 antitrypsin (rAAVSERPINA1) vectors in a nonhuman primate model: safety and immunologic aspects. Mol Ther 2002;6: 329-335.
89. Zhou S, Murphy J, Escobedo J, et al. Adenoassociated virus-mediated delivery of erythropoietin leads to sustained elevation of hematocrit in nonhuman primates. Gene Ther 1998;5: 665-670.
90. Li C, Hirsch M, Asokan A, 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;81:7540-7547.
91. Li H, Murphy SL, Giles-Davis W, et al. Pre-existing AAV capsid-specific CD8+ T cells are unable to eliminate AAV-transduced hepatocytes. Mol Ther 2007;15:792-800.
92. Wang L, Figueredo J, Calcedo R, et al. Crosspresentation of adeno-associated virus serotype 2 capsids activates cytotoxic T cells but does not render hepatocytes effective cytolytic targets. Hum Gene Ther 2007;18:185-194.
93. Li H, Tuyishime S, Wu T-L, et al. Adenoassociated virus vectors serotype 2 induce prolonged proliferation of capsid-specific CD8+ T cells in mice. Mol Ther 2011;19:536-546.
94. Martino AT, Basner-Tschakarjan E, Markusic DM, et al. Engineered AAV vector minimizes in vivo targeting of transduced hepatocytes by capsidspecific CD8+ T cells. Blood 2013;121:2224-2233.
95. Vercauteren K, Hoffman BE, Zolotukhin I, et al. Superior in vivo transduction of human hepatocytes using engineered AAV3 capsid. Mol Ther 2016;24: 1042-1049.
96. Lisowski L, Dane AP, Chu K, et al. Selection and evaluation of clinically relevant AAV variants in a xenograft liver model. Nature 2014;506:382-386.
97. 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 Invest 2009;119:2388-2398.
98. Hösel M, Broxtermann M, Janicki H, et al. Tolllike receptor 2-mediated innate immune response in human nonparenchymal liver cells toward adenoassociated viral vectors. Hepatology 2012;55: 287-297.
99. Jayandharan GR, Aslanidi G, Martino AT, et al. Activation of the NF-κB pathway by adenoassociated virus (AAV) vectors and its implications in immune response and gene therapy. Proc Natl Acad Sci 2011;108:3743-3748.
100. Sudres M, Ciré S, Vasseur V, et al. MyD88 signaling in B cells regulates the production of Th1-dependent antibodies to AAV. Mol Ther 2012; 20:1571-1581.
101. Martino AT, Suzuki M, Markusic DM, et al. The genome of self-complementary adeno-associated viral vectors increases Toll-like receptor 9-dependent innate immune responses in the liver. Blood 2011;117:6459-6468.
102. Zaiss AK, Cotter MJ, White LR, et al. Complement is an essential component of the immune response to adeno-associated virus vectors. J Virol 2008;82:2727-2740.
103. Zaiss A-K, Liu Q, Bowen GP, et al. Differential activation of innate immune responses by adenovirus and adeno-associated virus vectors. J Virol 2002;76:4580-4590.
104. Rogers GL, Shirley JL, Zolotukhin I, et al. Plasmacytoid and conventional dendritic cells cooperate in crosspriming AAV capsid-specific CD8+ T cells. Blood 2017;129:3184-3195.
105. Mingozzi F, Liu Y-L, Dobrzynski E, et al. Induction of immune tolerance to coagulation factor IX antigen by in vivo hepatic gene transfer. J Clin Invest 2003;111:1347-1356.
106. Dobrzynski E, Mingozzi F, Liu Y-L, et al. Induction of antigen-specific CD4+ T-cell anergy and deletion by in vivo viral gene transfer. Blood 2004;104: 969-977.
107. Franco LM, Sun B, Yang X, et al. Evasion of immune responses to introduced human acid αglucosidase by liver-restricted expression in glycogen storage disease type II. Mol Ther 2005;12: 876-884.
108. Ziegler RJ, Lonning SM, Armentano D, et al. AAV2 vector harboring a liver-restricted promoter facilitates sustained expression of therapeutic levels of α-galactosidase A and the induction of immune tolerance in Fabry mice. Mol Ther 2004;9:231-240.
109. Martino AT, Nayak S, Hoffman BE, et al. Tolerance induction to cytoplasmic β-galactosidase by hepatic AAV gene transfer-implications for antigen presentation and immunotoxicity. PLoS One 2009;4.
110. 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; 116:5842-5848.
111. Markusic DM, Hoffman BE, Perrin GQ, et al. Effective gene therapy for haemophilic mice with pathogenic factor IX antibodies. EMBO Mol Med 2013;5:1698-1709.
112. Han S, Ronzitti G, Arnson B, et al. Low-dose livertargeted gene therapy for Pompe disease enhances therapeutic efficacy of ERT via immune tolerance induction. Mol Ther Methods Clin Dev 2017;4: 126-136.
113. D'Avola D, López-Franco E, Sangro B, et al. Phase I open label liver-directed gene therapy clinical trial for acute intermittent porphyria. J Hepatol 2016;65:776-783.
114. Gao G, Lebherz C, Weiner DJ, et al. Erythropoietin gene therapy leads to autoimmune anemia in macaques. Blood 2004;103:3300-3302.
115. Herzog RW, Mount JD, Arruda VR, et al. Muscledirected gene transfer and transient immune suppression result in sustained partial correction of canine hemophilia B caused by a null mutation. Mol Ther 2001;4:192-200.
116. Wang Z, Kuhr CS, Allen JM, et al. Sustained AAV-mediated dystrophin expression in a canine model of Duchenne muscular dystrophy with a brief course of immunosuppression. Mol Ther J Am Soc Gene Ther 2007;15:1160-1166.
117. Mendell JR, Campbell K, Rodino-Klapac L, et al. Dystrophin immunity in Duchenne's muscular dystrophy. N Engl J Med 2010;363:1429-1437.
118. Flanigan KM, Campbell K, Viollet L, et al. Antidystrophin T cell responses in Duchenne muscular dystrophy: prevalence and a glucocorticoid treatment effect. Hum Gene Ther 2013;24:797-806.
119. Toromanoff A, Adjali O, Larcher T, et al. Lack of immunotoxicity after regional intravenous (RI) delivery of rAAV to nonhuman primate skeletal muscle. Mol Ther 2010;18:151-160.
120. Doerfler PA, Nayak S, Corti M, et al. Targeted approaches to induce immune tolerance for Pompe disease therapy. Mol Ther Methods Clin Dev 2016;3:15053.
121. Puzzo F, Colella P, Biferi MG, et al. Whole-body rescue of Pompe disease with AAV liver delivery of engineered secretable GAA transgenes. Sci Transl Med (in press).
122. Perrin GQ, Zolotukhin I, Sherman A, et al. Dynamics of antigen presentation to transgene product-specific CD4+ T cells and of Treg induction upon hepatic AAV gene transfer. Mol Ther Methods Clin Dev 2016;3:16083.
123. Faust SM, Bell P, Cutler BJ, et al. CpG-depleted adeno-associated virus vectors evade immune detection. J Clin Invest 2013;123:2994-3001.
124. Mingozzi F, Anguela XM, Pavani G, et al. Overcoming preexisting humoral immunity to AAV using capsid decoys. Sci Transl Med 2013;5: 194ra92.
125. Chapin J, Rottensteiner H, Scheiflinger F, et al. An analysis of bleeding rates and Factor IX consumption in the Phase I/II BAX 335 gene therapy trial in subjects with hemophilia B. Res Pract Thromb Haemost 2017;1:1-1451.
126. Simioni P, Tormene D, Tognin G, et al. X-linked thrombophilia with a mutant factor IX (factor IX Padua). N Engl J Med 2009;361:1671-1675.
127. George L, Giermasz A, Sullivan S, 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.
128. Miesbach W, Tangelder M, Meijer K, et al. Updated results from a dose escalation study in adults with severe or moderate-severe hemophilia B treated with AMT-060 (AAV5-hFIX) gene therapy: up to 1.5 years follow-up. Res Pract Thromb Haemost 2017;1:1-1451.
129. Pasi J, Rangarajan S, Walsh L, et al. Interim results from a Phase 1/2 AAV5-FVIII gene transfer in patients with severe hemophilia A. Res Pract Thromb Haemost 2017;1:1-1451.
130. Zinn E, Pacouret S, Khaychuk V, et al. In silico reconstruction of the viral evolutionary lineage yields a potent gene therapy vector. Cell Rep 2015; 12:1056-1068.
131. György B, Fitzpatrick Z, Crommentuijn MHW, et al. Naturally enveloped AAV vectors for shielding neutralizing antibodies and robust gene delivery in vivo. Biomaterials 2014;35: 7598-7609.
132. Tse LV, Klinc KA, Madigan VJ, et al. Structureguided evolution of antigenically distinct adenoassociated virus variants for immune evasion. Proc Natl Acad Sci U S A 2017;114:E4812-E4821.
133. 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 J Am Soc Gene Ther 2011; 19:2084-2091.
134. Chicoine LG, Montgomery CL, Bremer WG, et al. Plasmapheresis eliminates the negative impact of AAV antibodies on microdystrophin gene expression following vascular delivery. Mol Ther J Am Soc Gene Ther 2014;22:338-347.
135. Mimuro J, Mizukami H, Hishikawa S, et al. Minimizing the inhibitory effect of neutralizing antibody for efficient gene expression in the liver with adeno-associated virus 8 vectors. Mol Ther J Am Soc Gene Ther 2013;21:318-323.
136. Unzu C, Hervás-Stubbs S, Sampedro A, et al. Transient and intensive pharmacological immunosuppression fails to improve AAV-based liver gene transfer in non-human primates. J Transl Med 2012;10:122.