1932

Abstract

Immune responses in gene therapy with adeno-associated virus (AAV) vectors have been the object of almost two decades of study. Although preclinical models helped to define and predict certain aspects of interactions between the vector and the host immune system, most of our current knowledge has come from clinical trials. These studies have allowed development of effective interventions for modulating immunotoxicities associated with vector administration, resulting in therapeutic advances. However, the road to full understanding and effective modulation of immune responses in gene therapy is still long; the determinants of the balance between tolerance and immunogenicity in AAV vector–mediated gene transfer are not fully understood, and effective solutions for overcoming preexisting neutralizing antibodies are still lacking. However, despite these challenges, the goal of reliably delivering effective gene-based treatments is now in sight.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-virology-101416-041936
2017-09-29
2024-04-25
Loading full text...

Full text loading...

/deliver/fulltext/virology/4/1/annurev-virology-101416-041936.html?itemId=/content/journals/10.1146/annurev-virology-101416-041936&mimeType=html&fmt=ahah

Literature Cited

  1. Blacklow NR, Hoggan MD, Rowe WP. 1.  1967. Isolation of adenovirus-associated viruses from man. PNAS 58:1410–15 [Google Scholar]
  2. Sonntag F, Schmidt K, Kleinschmidt JA. 2.  2010. A viral assembly factor promotes AAV2 capsid formation in the nucleolus. PNAS 107:10220–25 [Google Scholar]
  3. Yan Z, Zak R, Zhang Y, Engelhardt JF. 3.  2004. Inverted terminal repeat sequences are important for intermolecular recombination and circularization of adeno-associated virus genomes. J. Virol. 79:364–79 [Google Scholar]
  4. Xiao X, Li J, Samulski RJ. 4.  1998. Production of high-titer recombinant adeno-associated virus vectors in the absence of helper adenovirus. J. Virol. 72:2224–32 [Google Scholar]
  5. Urabe M, Ding C, Kotin RM. 5.  2002. Insect cells as a factory to produce adeno-associated virus type 2 vectors. Hum. Gene Ther. 13:1935–43 [Google Scholar]
  6. van der Loo JCM, Wright JF. 6.  2016. Progress and challenges in viral vector manufacturing. Hum. Mol. Genet. 25:R42–52 [Google Scholar]
  7. Grieger JC, Soltys SM, Samulski RJ. 7.  2016. Production of recombinant adeno-associated virus vectors using suspension HEK293 cells and continuous harvest of vector from the culture media for GMP FIX and FLT1 clinical vector. Mol. Ther. 24:287–97 [Google Scholar]
  8. Summerford C, Samulski RJ. 8.  1998. Membrane-associated heparan sulfate proteoglycan is a receptor for adeno-associated virus type 2 virions. J. Virol. 72:1438–45 [Google Scholar]
  9. Pillay S, Meyer NL, Puschnik AS, Davulcu O, Diep J. 9.  et al. 2016. An essential receptor for adeno-associated virus infection. Nature 530:108–12 [Google Scholar]
  10. Ding W, Zhang L, Yan Z, Engelhardt JF. 10.  2005. Intracellular trafficking of adeno-associated viral vectors. Gene Ther 12:873–80 [Google Scholar]
  11. Mingozzi F, Maus MV, Hui DJ, Sabatino DE, Murphy SL. 11.  et al. 2007. CD8+ T-cell responses to adeno-associated virus capsid in humans. Nat. Med. 13:419–22 [Google Scholar]
  12. Veron P, Leborgne C, Monteilhet V, Boutin S, Martin S. 12.  et al. 2012. Humoral and cellular capsid-specific immune responses to adeno-associated virus type 1 in randomized healthy donors. J. Immunol. 188:6418–24 [Google Scholar]
  13. Hui DJ, Edmonson SC, Podsakoff GM, Pien GC, Ivanciu L. 13.  et al. 2015. AAV capsid CD8+ T-cell epitopes are highly conserved across AAV serotypes. Mol. Ther. Methods Clin. Dev. 2:15029 [Google Scholar]
  14. Flanigan KM, Campbell K, Viollet L, Wang W, Gomez AM. 14.  et al. 2013. Anti-dystrophin T cell responses in Duchenne muscular dystrophy: prevalence and a glucocorticoid treatment effect. Hum. Gene Ther. 24:797–806 [Google Scholar]
  15. Medawar PB. 15.  1948. Immunity to homologous grafted skin; the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br. J. Exp. Pathol. 29:58–69 [Google Scholar]
  16. Willett K, Bennett J. 16.  2013. Immunology of AAV-mediated gene transfer in the eye. Front. Immunol. 4:261 [Google Scholar]
  17. Bainbridge JWB, Smith AJ, Barker SS, Robbie S, Henderson R. 17.  et al. 2008. Effect of gene therapy on visual function in Leber's congenital amaurosis. N. Engl. J. Med. 358:2231–39 [Google Scholar]
  18. Maguire AM, Simonelli F, Pierce EA, Pugh EN, Mingozzi F. 18.  et al. 2008. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N. Engl. J. Med. 358:2240–48 [Google Scholar]
  19. Hauswirth WW, Aleman TS, Kaushal S, Cideciyan AV, Schwartz SB. 19.  et al. 2008. Treatment of Leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum. Gene Ther. 19:979–90 [Google Scholar]
  20. Bainbridge JWB, Mehat MS, Sundaram V, Robbie SJ, Barker SE. 20.  et al. 2015. Long-term effect of gene therapy on Leber's congenital amaurosis. N. Engl. J. Med. 372:1887–97 [Google Scholar]
  21. Russell S, Bennett J, Wellman JA, Chung DC, Yu ZF,. 21.  2017. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in subjects with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet https://doi.org/10.1016/S0140-6736(17)31868-8 [Crossref]
  22. Bennett J, Wellman J, Marshall KA, McCague S, Ashtari M. 22.  et al. 2016. Safety and durability of effect of contralateral-eye administration of AAV2 gene therapy in patients with childhood-onset blindness caused by RPE65 mutations: a follow-on phase 1 trial. Lancet 388:661–72 [Google Scholar]
  23. Amado D, Mingozzi F, Hui D, Bennicelli JL, Wei Z. 23.  et al. 2010. Safety and efficacy of subretinal readministration of a viral vector in large animals to treat congenital blindness. Sci. Translational Med. 2:21ra16 [Google Scholar]
  24. MacLachlan TK, Lukason M, Collins M, Munger R, Isenberger E. 24.  et al. 2011. Preclinical safety evaluation of AAV2-sFLT01—a gene therapy for age-related macular degeneration. Mol. Ther. 19:326–34 [Google Scholar]
  25. Uretsky S, Sahel JA, Galy A, Thomasson N, Honnet G. 25.  et al. 2015. A recombinant AAV2/2 carrying the wild-type ND4 gene for the treatment of LHON: preliminary results of a first-in-man study and upcoming pivotal efficacy trials Presented at 12th Int. Symp. Ocul. Pharmacol. Ther. (ISOPT Clin.), July 9–12, Berlin
  26. Mingozzi F, High KA. 26.  2011. Therapeutic in vivo gene transfer for genetic disease using AAV: progress and challenges. Nat. Rev. Genet. 12:341–55 [Google Scholar]
  27. Thomson AW, Knolle PA. 27.  2010. Antigen-presenting cell function in the tolerogenic liver environment. Nat. Rev. Immunol. 10:753–66 [Google Scholar]
  28. Lerut J, Sanchez-Fueyo A. 28.  2006. An appraisal of tolerance in liver transplantation. Am. J. Transplant. 6:1774–80 [Google Scholar]
  29. Topal E, Çatal F, Selimoğlu MA, Karabiber H, Klc T. 29.  et al. 2014. Acquired atopic disease after liver transplantation in children; similarities to and differences from adults. Eur. J. Gastroenterol. Hepatol. 26:1055–59 [Google Scholar]
  30. Mingozzi F, Hasbrouck NC, Basner-Tschakarjan E, Edmonson SA, Hui DJ. 30.  et al. 2007. Modulation of tolerance to the transgene product in a nonhuman primate model of AAV-mediated gene transfer to liver. Blood 110:2334–41 [Google Scholar]
  31. Mingozzi F, Liu YL, Dobrzynski E, Kaufhold A, Liu JH. 31.  et al. 2003. Induction of immune tolerance to coagulation factor IX antigen by in vivo hepatic gene transfer. J. Clin. Investig. 111:1347–56 [Google Scholar]
  32. Cao O, Dobrzynski E, Wang L, Nayak S, Mingle B. 32.  et al. 2007. Induction and role of regulatory CD4+CD25+ T cells in tolerance to the transgene product following hepatic in vivo gene transfer. Blood 110:1132–40 [Google Scholar]
  33. Lüth S, Huber S, Schramm C, Buch T, Zander S. 33.  et al. 2008. Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs. J. Clin. Investig. 118:3403–10 [Google Scholar]
  34. Follenzi A, Battaglia M, Lombardo A, Annoni A, Roncarolo MG, Naldini L. 34.  2004. Targeting lentiviral vector expression to hepatocytes limits transgene-specific immune response and establishes long-term expression of human antihemophilic factor IX in mice. Blood 103:3700–9 [Google Scholar]
  35. Markusic DM, Hoffman BE, Perrin GQ, Nayak S, Wang X. 35.  et al. 2013. Effective gene therapy for haemophilic mice with pathogenic factor IX antibodies. EMBO Mol. Med. 5:1698–709 [Google Scholar]
  36. Le Guen V, Judor JP, Boeffard F, Gauttier V, Ferry N. 36.  et al. 2017. Alloantigen gene transfer to hepatocytes promotes tolerance to pancreatic islet graft by inducing CD8+ regulatory T cells. J. Hepatol. 66:765–77 [Google Scholar]
  37. Breous E, Somanathan S, Wilson JM. 37.  2010. BALB/c mice show impaired hepatic tolerogenic response following AAV gene transfer to the liver. Mol. Ther. 18:766–74 [Google Scholar]
  38. D'Avola D, Lopez-Franco E, Sangro B, Pañeda A, Grossios N. 38.  et al. 2016. Phase I open label liver-directed gene therapy clinical trial for acute intermittent porphyria. J. Hepatol. 65:776–83 [Google Scholar]
  39. Manno CS, Arruda VR, Pierce GF, Glader B, Ragni M. 39.  et al. 2006. Successful transduction of liver in hemophilia by AAV-factor IX and limitations imposed by the host immune response. Nat. Med. 12:342–47 [Google Scholar]
  40. Nathwani AC, Tuddenham EGD, Rangarajan S, Rosales C, McIntosh J. 40.  et al. 2011. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N. Engl. J. Med. 365:2357–65 [Google Scholar]
  41. Nathwani AC, Reiss UM, Tuddenham EGD, Rosales C, Chowdary P. 41.  et al. 2014. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N. Engl. J. Med. 371:1994–2004 [Google Scholar]
  42. Zhu J, Huang X, Yang Y. 42.  2009. The TLR9-MyD88 pathway is critical for adaptive immune responses to adeno-associated virus gene therapy vectors in mice. J. Clin. Investig. 119:2388–98 [Google Scholar]
  43. Sudres M, Ciré S, Vasseur V, Brault L, Da Rocha S. 43.  et al. 2012. MyD88 signaling in B cells regulates the production of Th1-dependent antibodies to AAV. Mol. Ther. 20:1571–81 [Google Scholar]
  44. Rogers GL, Martino AT, Aslanidi GV, Jayandharan GR, Srivastava A, Herzog RW. 44.  2011. Innate immune responses to AAV vectors. Front. Microbiol. 2:194 [Google Scholar]
  45. Martino AT, Suzuki M, Markusic DM, Zolotukhin I, Ryals RC. 45.  et al. 2011. The genome of self-complementary adeno-associated viral vectors increases Toll-like receptor 9-dependent innate immune responses in the liver. Blood 117:6459–68 [Google Scholar]
  46. Hösel M, Broxtermann M, Janicki H, Esser K, Arzberger S. 46.  et al. 2011. Toll-like receptor 2-mediated innate immune response in human nonparenchymal liver cells toward adeno-associated viral vectors. Hepatology 55:287–97 [Google Scholar]
  47. Douar AM, Poulard K, Stockholm D, Danos O. 47.  2001. Intracellular trafficking of adeno-associated virus vectors: routing to the late endosomal compartment and proteasome degradation. J. Virol. 75:1824–33 [Google Scholar]
  48. Yan Z, Zak R, Luxton GWG, Ritchie TC, Bantel-Schaal U, Engelhardt JF. 48.  2002. Ubiquitination of both adeno-associated virus type 2 and 5 capsid proteins affects the transduction efficiency of recombinant vectors. J. Virol. 76:2043–53 [Google Scholar]
  49. Finn JD, Hui D, Downey HD, Dunn D, Pien GC. 49.  et al. 2010. Proteasome inhibitors decrease AAV2 capsid derived peptide epitope presentation on MHC class I following transduction. Mol. Ther. 18:135–42 [Google Scholar]
  50. Vandenberghe LH, Wang L, Somanathan S, Zhi Y, Figueredo J. 50.  et al. 2006. Heparin binding directs activation of T cells against adeno-associated virus serotype 2 capsid. Nat. Med. 12:967–71 [Google Scholar]
  51. Chadeuf G, Ciron C, Moullier P, Salvetti A. 51.  2005. Evidence for encapsidation of prokaryotic sequences during recombinant adeno-associated virus production and their in vivo persistence after vector delivery. Mol. Ther. 12:744–53 [Google Scholar]
  52. Hauck B, Murphy SL, Smith PH, Qu G, Liu X. 52.  et al. 2009. Undetectable transcription of cap in a clinical AAV vector: implications for preformed capsid in immune responses. Mol. Ther. 17:144–52 [Google Scholar]
  53. George LA, Sullivan SK, Giermasz A, Ducore JM, Teitel JM. 53.  et al. 2016. SPK-9001: adeno-associated virus mediated gene transfer for hemophilia B achieves sustained mean factor IX activity levels of >30% without immunosuppression. Blood 128:3 [Google Scholar]
  54. Li C, Goudy K, Hirsch M, Asokan A, Fan Y. 54.  et al. 2009. Cellular immune response to cryptic epitopes during therapeutic gene transfer. PNAS 106:10770–74 [Google Scholar]
  55. Li C, Hirsch M, DiPrimio N, Asokan A, Goudy K. 55.  et al. 2009. Cytotoxic-T-lymphocyte-mediated elimination of target cells transduced with engineered adeno-associated virus type 2 vector in vivo. J. Virol. 83:6817–24 [Google Scholar]
  56. Wang L, Figueredo J, Calcedo R, Lin J, Wilson JM. 56.  2007. Cross-presentation of adeno-associated virus serotype 2 capsids activates cytotoxic T cells but does not render hepatocytes effective cytolytic targets. Hum. Gene Ther. 18:185–94 [Google Scholar]
  57. Asokan A, Conway JC, Phillips JL, Li C, Hegge J. 57.  et al. 2010. Reengineering a receptor footprint of adeno-associated virus enables selective and systemic gene transfer to muscle. Nat. Biotechnol. 28:79–82 [Google Scholar]
  58. Li C, Hirsch M, Asokan A, Zeithaml B, Ma H. 58.  et al. 2007. Adeno-associated virus type 2 (AAV2) capsid-specific cytotoxic T lymphocytes eliminate only vector-transduced cells coexpressing the AAV2 capsid in vivo. J. Virol. 81:7540–47 [Google Scholar]
  59. Martino AT, Basner-Tschakarjan E, Markusic DM, Finn JD, Hinderer C. 59.  et al. 2013. Engineered AAV vector minimizes in vivo targeting of transduced hepatocytes by capsid-specific CD8+ T cells. Blood 121:2224–33 [Google Scholar]
  60. Wu TL, Li H, Faust SM, Chi E, Zhou S. 60.  et al. 2014. CD8+ T cell recognition of epitopes within the capsid of adeno-associated virus 8-based gene transfer vectors depends on vectors’ genome. Mol. Ther. 22:42–51 [Google Scholar]
  61. Nguyen DH, Hurtado-Ziola N, Gagneux P, Varki A. 61.  2006. Loss of Siglec expression on T lymphocytes during human evolution. PNAS 103:7765–70 [Google Scholar]
  62. Li H, Lasaro MO, Jia B, Lin SW, Haut LH. 62.  et al. 2011. Capsid-specific T-cell responses to natural infections with adeno-associated viruses in humans differ from those of nonhuman primates. Mol. Ther. 19:2021–30 [Google Scholar]
  63. Pien GC, Basner-Tschakarjan E, Hui DJ, Mentlik AN, Finn JD. 63.  et al. 2009. Capsid antigen presentation flags human hepatocytes for destruction after transduction by adeno-associated viral vectors. J. Clin. Investig. 119:1688–95 [Google Scholar]
  64. Scholten KBJ, Schreurs MWJ, Ruizendaal JJ, Kueter EWM, Kramer D. 64.  et al. 2005. Preservation and redirection of HPV16E7-specific T cell receptors for immunotherapy of cervical cancer. Clin. Immunol. 114:119–29 [Google Scholar]
  65. Faust SM, Bell P, Cutler BJ, Ashley SN, Zhu Y. 65.  et al. 2013. CpG-depleted adeno-associated virus vectors evade immune detection. J. Clin. Investig. 123:2994–3001 [Google Scholar]
  66. Mingozzi F, Anguela XM, Pavani G, Chen Y, Davidson RJ. 66.  et al. 2013. Overcoming preexisting humoral immunity to AAV using capsid decoys. Sci. Transl. Med. 5:194ra92 [Google Scholar]
  67. Schwartz M, Deczkowska A. 67.  2016. Neurological disease as a failure of brain-immune crosstalk: the multiple faces of neuroinflammation. Trends Immunol 37:668–79 [Google Scholar]
  68. Kamran N, Calinescu A, Candolfi M, Chandran M, Mineharu Y. 68.  et al. 2016. Recent advances and future of immunotherapy for glioblastoma. Expert Opin. Biol. Ther. 16:1245–64 [Google Scholar]
  69. Sagar D, Foss C, El Baz R, Pomper MG, Khan ZK, Jain P. 69.  2011. Mechanisms of dendritic cell trafficking across the blood-brain barrier. J. Neuroimmune Pharmacol. 7:74–94 [Google Scholar]
  70. Rudolph H, Klopstein A, Gruber I, Blatti C, Lyck R, Engelhardt B. 70.  2016. Postarrest stalling rather than crawling favors CD8+ over CD4+ T-cell migration across the blood-brain barrier under flow in vitro. Eur. J. Immunol. 46:2187–203 [Google Scholar]
  71. Sessa M, Lorioli L, Fumagalli F, Acquati S, Redaelli D. 71.  et al. 2016. Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial. Lancet 388:476–87 [Google Scholar]
  72. Biffi A, Montini E, Lorioli L, Cesani M, Fumagalli F. 72.  et al. 2013. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science 341:1233158 [Google Scholar]
  73. Hocquemiller M, Giersch L, Audrain M, Parker S, Cartier N. 73.  2016. Adeno-associated virus-based gene therapy for CNS diseases. Hum. Gene Ther. 27:478–96 [Google Scholar]
  74. Kaplitt MG, Feigin A, Tang C, Fitzsimons HL, Mattis P. 74.  et al. 2007. Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson's disease: an open label, phase I trial. Lancet 369:2097–105 [Google Scholar]
  75. Leone P, Shera D, McPhee SWJ, Francis JS, Kolodny EH. 75.  et al. 2012. Long-term follow-up after gene therapy for Canavan disease. Sci. Transl. Med. 4:165ra163 [Google Scholar]
  76. McPhee SWJ, Janson CG, Li C, Samulski RJ, Camp AS. 76.  et al. 2006. Immune responses to AAV in a phase I study for Canavan disease. J. Gene Med. 8:577–88 [Google Scholar]
  77. Worgall S, Sondhi D, Hackett NR, Kosofsky B, Kekatpure MV. 77.  et al. 2008. Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA. Hum. Gene Ther. 19:463–74 [Google Scholar]
  78. Hwu WL, Muramatsu SI, Tseng SH, Tzen KY, Lee NC. 78.  et al. 2012. Gene therapy for aromatic l-amino acid decarboxylase deficiency. Sci. Transl. Med. 4:134ra61 [Google Scholar]
  79. Ellinwood NM, Ausseil J, Desmaris N, Bigou S, Liu S. 79.  et al. 2011. Safe, efficient, and reproducible gene therapy of the brain in the dog models of Sanfilippo and Hurler syndromes. Mol. Ther. 19:251–59 [Google Scholar]
  80. Haurigot V, Marcó S, Ribera A, Garcia M, Ruzo A. 80.  et al. 2013. Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy. J. Clin. Investig. 123:3254–71 [Google Scholar]
  81. Cearley CN, Wolfe JH. 81.  2006. Transduction characteristics of adeno-associated virus vectors expressing cap serotypes 7, 8, 9, and Rh10 in the mouse brain. Mol Ther 13:528–37 [Google Scholar]
  82. Foust KD, Nurre E, Montgomery CL, Hernandez A, Chan CM, Kaspar BK. 82.  2009. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat. Biotechnol. 27:59–65 [Google Scholar]
  83. Duque S, Joussemet B, Rivière C, Marais T, Dubreil L. 83.  et al. 2009. Intravenous administration of self-complementary AAV9 enables transgene delivery to adult motor neurons. Mol. Ther. 17:1187–96 [Google Scholar]
  84. Deverman BE, Pravdo PL, Simpson BP, Kumar SR, Chan KY. 84.  et al. 2016. Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain. Nat. Biotechnol. 34:204–9 [Google Scholar]
  85. Hudry E, Martin C, Gandhi S, György B, Scheffer DI. 85.  et al. 2016. Exosome-associated AAV vector as a robust and convenient neuroscience tool. Gene Ther 23:380–92 [Google Scholar]
  86. 86.  Deleted in proof
  87. Foster H, Sharp PS, Athanasopoulos T, Trollet C, Graham IR. 87.  et al. 2008. Codon and mRNA sequence optimization of microdystrophin transgenes improves expression and physiological outcome in dystrophic mdx mice following AAV2/8 gene transfer. Mol. Ther. 16:1825–32 [Google Scholar]
  88. Fraites TJ Jr., Schleissing MR, Shanely RA, Walter GA, Cloutier DA. 88.  et al. 2002. Correction of the enzymatic and functional deficits in a model of Pompe disease using adeno-associated virus vectors. Mol. Ther. 5:571–78 [Google Scholar]
  89. Lai Y, Yue Y, Liu M, Ghosh A, Engelhardt JF. 89.  et al. 2005. Efficient in vivo gene expression by trans-splicing adeno-associated viral vectors. Nat. Biotechnol. 23:1435–39 [Google Scholar]
  90. Le Guiner C, Montus M, Servais L, Chérel Y, Francois V. 90.  et al. 2014. Forelimb treatment in a large cohort of dystrophic dogs supports delivery of a recombinant AAV for exon skipping in Duchenne patients. Mol. Ther. 22:1923–35 [Google Scholar]
  91. Lostal W, Bartoli M, Bourg N, Roudaut C, Bentaib A. 91.  et al. 2010. Efficient recovery of dysferlin deficiency by dual adeno-associated vector-mediated gene transfer. Hum. Mol. Genet. 19:1897–907 [Google Scholar]
  92. Louboutin JP, Wang L, Wilson JM. 92.  2005. Gene transfer into skeletal muscle using novel AAV serotypes. J. Gene Med. 7:442–51 [Google Scholar]
  93. Ross CJD, Twisk J, Bakker AC, Miao F, Verbart D. 93.  et al. 2006. Correction of feline lipoprotein lipase deficiency with adeno-associated virus serotype 1-mediated gene transfer of the lipoprotein lipase S447X beneficial mutation. Hum. Gene Ther. 17:487–99 [Google Scholar]
  94. Song S, Morgan M, Ellis T, Poirier A, Chesnut K. 94.  et al. 1998. Sustained secretion of human alpha-1-antitrypsin from murine muscle transduced with adeno-associated virus vectors. PNAS 95:14384–88 [Google Scholar]
  95. Wang B, Li J, Xiao X. 95.  2000. Adeno-associated virus vector carrying human minidystrophin genes effectively ameliorates muscular dystrophy in mdx mouse model. PNAS 97:13714–19 [Google Scholar]
  96. Gregorevic P, Allen JM, Minami E, Blankinship MJ, Haraguchi M. 96.  et al. 2006. RAAV6-microdystrophin preserves muscle function and extends lifespan in severely dystrophic mice. Nat. Med. 12:787–89 [Google Scholar]
  97. Kessler PD, Podsakoff GM, Chen X, McQuiston SA, Colosi PC. 97.  et al. 1996. Gene delivery to skeletal muscle results in sustained expression and systemic delivery of a therapeutic protein. PNAS 93:14082–87 [Google Scholar]
  98. Xiao X, Li J, Samulski RJ. 98.  1996. Efficient long-term gene transfer into muscle tissue of immunocompetent mice by adeno-associated virus vector. J. Virol. 70:8098–108 [Google Scholar]
  99. Herzog RW, Hagstrom JN, Kung SH, Tai SJ, Wilson JM. 99.  et al. 1997. Stable gene transfer and expression of human blood coagulation factor IX after intramuscular injection of recombinant adeno-associated virus. PNAS 94:5804–9 [Google Scholar]
  100. Gaudet D, Stroes ES, Methot J, Brisson D, Tremblay K. 100.  et al. 2016. Long-term retrospective analysis of gene therapy with alipogene tiparvovec and its effect on lipoprotein lipase deficiency-induced pancreatitis. Hum. Gene Ther. 27:916–25 [Google Scholar]
  101. Mueller C, Chulay JD, Trapnell BC, Humphries M, Carey B. 101.  et al. 2013. Human Treg responses allow sustained recombinant adeno-associated virus-mediated transgene expression. J. Clin. Investig. 123:5310–18 [Google Scholar]
  102. Buchlis G, Podsakoff GM, Radu A, Hawk SM, Flake AW. 102.  et al. 2012. Factor IX expression in skeletal muscle of a severe hemophilia B patient 10 years after AAV-mediated gene transfer. Blood 119:3038–41 [Google Scholar]
  103. Mack DL, Poulard K, Goddard MA, Latournerie V, Snyder JM. 103.  et al. 2017. Systemic AAV8-mediated gene therapy drives whole-body correction of myotubular myopathy in dogs. Mol. Ther. 25:839–54 [Google Scholar]
  104. Guiner CL, Servais L, Montus M, Larcher T, Fraysse B. 104.  et al. 2016. 503. Adeno-associated virus vector (AAV) microdystrophin gene therapy prolongs survival and restores muscle function in the canine model of Duchenne muscular dystrophy (DMD). Mol. Ther. 24:S200 [Google Scholar]
  105. Matzinger P. 105.  2002. The danger model: a renewed sense of self. Science 296:301–5 [Google Scholar]
  106. Mendell JR, Campbell K, Rodino-Klapac L, Sahenk Z, Shilling C. 106.  et al. 2010. Dystrophin immunity in Duchenne's muscular dystrophy. N. Engl. J. Med. 363:1429–37 [Google Scholar]
  107. Haurigot V, Mingozzi F, Buchlis G, Hui DJ, Chen Y. 107.  et al. 2010. Safety of AAV factor IX peripheral transvenular gene delivery to muscle in hemophilia B dogs. Mol. Ther. 18:1318–29 [Google Scholar]
  108. Toromanoff A, Adjali O, Larcher T, Hill M, Guigand L. 108.  et al. 2010. Lack of immunotoxicity after regional intravenous (RI) delivery of rAAV to nonhuman primate skeletal muscle. Mol. Ther. 18:151–60 [Google Scholar]
  109. Herzog RW, Fields PA, Arruda VR, Brubaker JO, Armstrong E. 109.  et al. 2002. Influence of vector dose on factor IX-specific T and B cell responses in muscle-directed gene therapy. Hum. Gene Ther. 13:1281–91 [Google Scholar]
  110. Rogers GL, Martino AT, Zolotukhin I, Ertl HC, Herzog RW. 110.  2014. Role of the vector genome and underlying factor IX mutation in immune responses to AAV gene therapy for hemophilia B. J. Transl. Med. 12:25 [Google Scholar]
  111. Kishnani PS, Goldenberg PC, DeArmey SL, Heller J, Benjamin D. 111.  et al. 2010. Cross-reactive immunologic material status affects treatment outcomes in Pompe disease infants. Mol. Genet. Metab. 99:26–33 [Google Scholar]
  112. Falk DJ, Soustek MS, Todd AG, Mah CS, Cloutier DA. 112.  et al. 2015. Comparative impact of AAV and enzyme replacement therapy on respiratory and cardiac function in adult Pompe mice. Mol. Ther. Methods Clin. Dev. 2:15007 [Google Scholar]
  113. Mingozzi F, Meulenberg JJ, Hui DJ, Basner-Tschakarjan E, Hasbrouck NC. 113.  et al. 2009. AAV-1-mediated gene transfer to skeletal muscle in humans results in dose-dependent activation of capsid-specific T cells. Blood 114:2077–86 [Google Scholar]
  114. Mendell JR, Sahenk Z, Malik V, Gomez AM, Flanigan KM. 114.  et al. 2015. A phase 1/2a follistatin gene therapy trial for Becker muscular dystrophy. Mol. Ther. 23:192–201 [Google Scholar]
  115. Ferreira V, Twisk J, Kwikkers K, Aronica E, Brisson D. 115.  et al. 2014. Immune responses to intramuscular administration of alipogene tiparvovec (AAV1-LPL S447X) in a phase II clinical trial of lipoprotein lipase deficiency gene therapy. Hum. Gene Ther. 25:180–88 [Google Scholar]
  116. Ferreira V, Petry H, Salmon F. 116.  2014. Immune responses to AAV-vectors, the Glybera example from bench to bedside. Front. Immunol. 5:82 [Google Scholar]
  117. Brantly ML, Chulay JD, Wang L, Mueller C, Humphries M. 117.  et al. 2009. Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy. PNAS 106:16363–68 [Google Scholar]
  118. Flotte TR, Trapnell BC, Humphries M, Carey B, Calcedo R. 118.  et al. 2011. Phase 2 clinical trial of a recombinant adeno-associated viral vector expressing α1-antitrypsin: interim results. Hum. Gene Ther. 22:1239–47 [Google Scholar]
  119. Calcedo R, Somanathan S, Qin Q, Betts MR, Rech AJ. 119.  et al. 2017. Class I-restricted T-cell responses to a polymorphic peptide in a gene therapy clinical trial for α-1-antitrypsin deficiency. PNAS 114:1655–59 [Google Scholar]
  120. Velazquez VM, Bowen DG, Walker CM. 120.  2009. Silencing of T lymphocytes by antigen-driven programmed death in recombinant adeno-associated virus vector-mediated gene therapy. Blood 113:538–45 [Google Scholar]
  121. Calcedo R, Morizono H, Wang L, McCarter R, He J. 121.  et al. 2011. Adeno-associated virus antibody profiles in newborns, children, and adolescents. Clin. Vaccine Immunol. 18:1586–88 [Google Scholar]
  122. Erles K, Sebokova P, Schlehofer JR. 122.  1999. Update on the prevalence of serum antibodies (IgG and IgM) to adeno-associated virus (AAV). J. Med. Virol 59406–11 [Google Scholar]
  123. Li C, Narkbunnam N, Samulski RJ, Asokan A, Hu G. 123.  et al. 2011. Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia. Gene Ther 19:288–94 [Google Scholar]
  124. Gao GP, Alvira MR, Wang L, Calcedo R, Johnston J, Wilson JM. 124.  2002. Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. PNAS 99:11854–59 [Google Scholar]
  125. Boutin S, Monteilhet V, Veron P, Leborgne C, Benveniste O. 125.  et al. 2010. 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. 21:704–12 [Google Scholar]
  126. Jiang H, Couto LB, Patarroyo-White S, Liu T, Nagy D. 126.  et al. 2006. Effects of transient immunosuppression on adenoassociated, virus-mediated, liver-directed gene transfer in rhesus macaques and implications for human gene therapy. Blood 108:3321–28 [Google Scholar]
  127. Scallan CD, Jiang H, Liu T, Patarroyo-White S, Sommer JM. 127.  et al. 2006. Human immunoglobulin inhibits liver transduction by AAV vectors at low AAV2 neutralizing titers in SCID mice. Blood 107:1810–17 [Google Scholar]
  128. Meliani A, Leborgne C, Triffault S, Jeanson-Leh L, Veron P, Mingozzi F. 128.  2015. Determination of anti-adeno-associated virus vector neutralizing antibody titer with an in vitro reporter system. Hum. Gene Ther. Methods 26:45–53 [Google Scholar]
  129. Manno CS, Chew AJ, Hutchison S, Larson PJ, Herzog RW. 129.  et al. 2002. AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood 101:2963–72 [Google Scholar]
  130. Monahan PE. 130.  2015. Gene therapy in an era of emerging treatment options for hemophilia B. J. Thromb. Haemost. 13:Suppl. 1S151–60 [Google Scholar]
  131. Miesbach W, Tangelder M, Klamroth R, Schutgens R, Coppens M. 131.  et al. 2016. Updated results from a dose escalating study in adult patients with haemophilia B treated with AMT-060 (AAV5-hFIX) gene therapy. Haemophilia 22:Suppl. 4151–52 [Google Scholar]
  132. 132. Dimension Ther. 2017. Dimension announces interim topline results from ongoing phase 1/2 clinical program for DTX101, Dimension's lead AAV product candidate in development for adult patients with moderate/severe to severe hemophilia B Press Release, Jan. 31. http://investors.dimensiontx.com/phoenix.zhtml?c=254192&p=irol-newsArticle&ID=2240877
  133. Pasi J, Wong W, Rangarajan S. 133.  2016. Interim results of an open-label, phase 1/2 study of BMN 270, an AAV5-FVIII gene transfer in severe hemophilia A. Haemophilia 22:Suppl. 4151–52 [Google Scholar]
  134. Chicoine LG, Montgomery CL, Bremer WG, Shontz KM, Griffin DA. 134.  et al. 2014. Plasmapheresis eliminates the negative impact of aav antibodies on microdystrophin gene expression following vascular delivery. Mol. Ther. 22:338–47 [Google Scholar]
  135. Monteilhet V, Saheb S, Boutin S, Leborgne C, Veron P. 135.  et al. 2011. 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. 19:2084–91 [Google Scholar]
  136. Kishimoto TK, Ferrari JD, LaMothe RA, Kolte PN, Griset AP. 136.  et al. 2016. Improving the efficacy and safety of biologic drugs with tolerogenic nanoparticles. Nat. Nanotechnol. 11:890–99 [Google Scholar]
  137. Mingozzi F, Chen Y, Murphy SL, Edmonson SC, Tai A. 137.  et al. 2012. Pharmacological modulation of humoral immunity in a nonhuman primate model of AAV gene transfer for hemophilia B. Mol. Ther. 20:1410–16 [Google Scholar]
  138. Unzu C, Hervás-Stubbs S, Sampedro A, Mauleon I, Mancheño U. 138.  et al. 2012. Transient and intensive pharmacological immunosuppression fails to improve AAV-based liver gene transfer in non-human primates. J. Transl. Med. 10:122 [Google Scholar]
  139. Montenegro-Miranda PS, Bloemendaal LT, Kunne C, De Waart DR, Bosma PJ. 139.  2011. Mycophenolate mofetil impairs transduction of single-stranded adeno-associated viral vectors. Hum. Gene Ther. 22:605–12 [Google Scholar]
  140. Mingozzi F, Chen Y, Edmonson SC, Zhou S, Thurlings RM. 140.  et al. 2013. Prevalence and pharmacological modulation of humoral immunity to AAV vectors in gene transfer to synovial tissue. Gene Ther 20:417–24 [Google Scholar]
  141. Mimuro J, Mizukami H, Hishikawa S, Ikemoto T, Ishiwata A. 141.  et al. 2013. Minimizing the inhibitory effect of neutralizing antibody for efficient gene expression in the liver with adeno-associated virus 8 vectors. Mol. Ther. 21:318–23 [Google Scholar]
/content/journals/10.1146/annurev-virology-101416-041936
Loading
/content/journals/10.1146/annurev-virology-101416-041936
Loading

Data & Media loading...

  • 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