Gene therapy for monogenic liver diseases: clinical successes, current challenges and future prospects

Journal of Inherited Metabolic Disease

Volumn 40, Issue 4, 2017, Pages 497-517

  Baruteau, Julien ^a,b,c   Waddington, Simon N ^c,d   Alexander, Ian E ^e,f   Gissen, Paul ^a,b,c  

^a UNIVERSITY COLLEGE LONDON   (United Kingdom)

^b GREAT ORMOND STREET HOSPITAL   (United Kingdom)

^c UNIVERSITY COLLEGE LONDON   (United Kingdom)

^d UNIVERSITY OF THE WITWATERSRAND   (South Africa)

^e CHILDREN S HOSPITAL AT WESTMEAD   (Australia)

^f UNIVERSITY OF SYDNEY   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

ADENO ASSOCIATED VIRUS VECTOR; ADENOVIRUS VECTOR; RETROVIRUS VECTOR; BLOOD CLOTTING FACTOR 9; COMPLEMENTARY DNA;

ADAPTIVE IMMUNITY; ARTICLE; ECONOMIC MODEL; GENE EXPRESSION; GENE THERAPY; GENE TRANSFER; HEALTH CARE; HUMAN; IMMUNE RESPONSE; IMMUNOLOGICAL MEMORY; LIVER CELL; LIVER DISEASE; MONOGENIC DISORDER; MUTAGENESIS; NONHUMAN; RISK BENEFIT ANALYSIS; TARGET CELL; TARGET ORGAN; TRANSGENE; ADENOVIRIDAE; ANIMAL; DEPENDOPARVOVIRUS; GENE VECTOR; GENETICS; HEMOPHILIA A; HEMOPHILIA B; IMMUNE SYSTEM; LIVER; METABOLISM; RETROVIRIDAE; TREATMENT OUTCOME;

ADENOVIRIDAE; ANIMALS; DEPENDOVIRUS; DNA, COMPLEMENTARY; FACTOR IX; GENE TRANSFER TECHNIQUES; GENETIC THERAPY; GENETIC VECTORS; HEMOPHILIA A; HEMOPHILIA B; HUMANS; IMMUNE SYSTEM; LIVER; LIVER DISEASES; MUTAGENESIS; RETROVIRIDAE; TRANSGENES; TREATMENT OUTCOME;

EID: 85020105413     PISSN: 01418955     EISSN: 15732665     Source Type: Journal    
DOI: 10.1007/s10545-017-0053-3     Document Type: Article

References (238)

1. Alba R, Bosch A, Chillon M (2005) Gutless adenovirus: last-generation adenovirus for gene therapy. Gene Ther 12(Suppl 1):S18–S27
2. Andrews JL, Kadan MJ, Gorziglia MI, Kaleko M, Connelly S (2001) Generation and characterization of E1/E2a/E3/E4-deficient adenoviral vectors encoding human factor VIII. Mol Ther 3:329–336
3. Angelis A, Tordrup D, Kanavos P (2015) Socio-economic burden of rare diseases: a systematic review of cost of illness evidence. Health Policy 119:964–979
4. Annoni A, Goudy K, Akbarpour M, Naldini L, Roncarolo MG (2013) Immune responses in liver-directed lentiviral gene therapy. Transl Res 161:230–240
5. Apolonia L, Waddington SN, Fernandes C et al (2007) Stable gene transfer to muscle using non-integrating lentiviral vectors. Mol Ther 15:1947–1954
6. Armstrong EP, Malone DC, Krishnan S, Wessler MJ (2014) Costs and utilization of hemophilia a and B patients with and without inhibitors. J Med Econ 17:798–802
7. Arruda VR, Fields PA, Milner R et al (2001) Lack of germline transmission of vector sequences following systemic administration of recombinant AAV-2 vector in males. Mol Ther 4:586–592
8. Atchison RW, Casto BC, Hammon WM (1965) Adenovirus-associated defective virus particles. Science 149:754–756
9. Azuma H, Paulk N, Ranade A et al (2007) Robust expansion of human hepatocytes in fah−/−/Rag2−/−/Il2rg−/− mice. Nat Biotechnol 25:903–910
10. Bainbridge JW, Smith AJ, Barker SS et al (2008) Effect of gene therapy on visual function in Leber’s congenital amaurosis. N Engl J Med 358:2231–2239
11. Baruteau J, Waddington SN, Alexander IE, Gissen P (2017) Delivering efficient liver-directed AAV-mediated gene therapy. Gene Ther. doi:10.1038/gt.2016.90
12. Basner-Tschakarjan E, Mingozzi F (2014) Cell-mediated immunity to AAV vectors, evolving concepts and potential solutions. Front Immunol 5:350
13. Belalcazar LM, Merched A, Carr B et al (2003) Long-term stable expression of human apolipoprotein A-I mediated by helper-dependent adenovirus gene transfer inhibits atherosclerosis progression and remodels atherosclerotic plaques in a mouse model of familial hypercholesterolemia. Circulation 107:2726–2732
14. Bell P, Wang L, Gao G et al (2011) Inverse zonation of hepatocyte transduction with AAV vectors between mice and non-human primates. Mol Genet Metab 104:395–403
15. Benihoud K, Yeh P, Perricaudet M (1999) Adenovirus vectors for gene delivery. Curr Opin Biotechnol 10:440–447
16. Berns KI, Byrne BJ, Flotte TR et al (2015) Adeno-associated virus type 2 and hepatocellular carcinoma? Hum Gene Ther 26:779–781
17. Berry GE, Asokan A (2016) Cellular transduction mechanisms of adeno-associated viral vectors. Curr Opin Virol 21:54–60
18. Bessis N, GarciaCozar FJ, Boissier MC (2004) Immune responses to gene therapy vectors: influence on vector function and effector mechanisms. Gene Ther 11(Suppl 1):S10–S17
19. Biffi A, Montini E, Lorioli L et al (2013) Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science 341:1233158
20. Blaese RM, Culver KW, Miller AD et al (1995) T lymphocyte-directed gene therapy for ADA-SCID: initial trial results after 4 years. Science 270:475–480
21. Booth C, Gaspar HB, Thrasher AJ (2016) Treating immunodeficiency through HSC Gene therapy. Trends Mol Med 22:317–327
22. Bordignon C, Notarangelo LD, Nobili N et al (1995) Gene therapy in peripheral blood lymphocytes and bone marrow for ADA- immunodeficient patients. Science 270:470–475
23. Boutin S, Monteilhet V, Veron P 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 21:704–712
24. Brantly ML, Spencer LT, Humphries M et al (2006) Phase I trial of intramuscular injection of a recombinant adeno-associated virus serotype 2 alphal-antitrypsin (AAT) vector in AAT-deficient adults. Hum Gene Ther 17:1177–1186
25. Brantly ML, Chulay JD, Wang L et al (2009) Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy. Proc Natl Acad Sci USA 106:16363–16368
26. Breous E, Somanathan S, Vandenberghe LH, Wilson JM (2009) Hepatic regulatory T cells and Kupffer cells are crucial mediators of systemic T cell tolerance to antigens targeting murine liver. Hepatology 50:612–621
27. Brown BD, Shi CX, Powell S, Hurlbut D, Graham FL, Lillicrap D (2004) Helper-dependent adenoviral vectors mediate therapeutic factor VIII expression for several months with minimal accompanying toxicity in a canine model of severe hemophilia a. Blood 103:804–810
28. Brunetti-Pierri N, Ng P (2011) Helper-dependent adenoviral vectors for liver-directed gene therapy. Hum Mol Genet 20:R7–13
29. Brunetti-Pierri N, Palmer DJ, Beaudet AL, Carey KD, Finegold M, Ng P (2004) Acute toxicity after high-dose systemic injection of helper-dependent adenoviral vectors into nonhuman primates. Hum Gene Ther 15:35–46
30. Brunetti-Pierri N, Nichols TC, McCorquodale S et al (2005) Sustained phenotypic correction of canine hemophilia B after systemic administration of helper-dependent adenoviral vector. Hum Gene Ther 16:811–820
31. Brunetti-Pierri N, Ng T, Iannitti DA et al (2006) Improved hepatic transduction, reduced systemic vector dissemination, and long-term transgene expression by delivering helper-dependent adenoviral vectors into the surgically isolated liver of nonhuman primates. Hum Gene Ther 17:391–404
32. Bryant LM, Christopher DM, Giles AR et al (2013) Lessons learned from the clinical development and market authorization of Glybera. Hum Gene Ther Clin Dev 24:55–64
33. Buchlis G, Podsakoff GM, Radu A et al (2012) Factor IX expression in skeletal muscle of a severe hemophilia B patient 10 years after AAV-mediated gene transfer. Blood 119:3038–3041
34. Buning H, Schmidt M (2015) Adeno-associated vector toxicity-to be or not to be? Mol Ther 23:1673–1675
35. Calcedo R, Wilson JM (2013) Humoral immune response to AAV. Front Immunol 4:341
36. Calcedo R, Vandenberghe LH, Gao G, Lin J, Wilson JM (2009) Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. J Infect Dis 199:381–390
37. Calcedo R, Morizono H, Wang L et al (2011) Adeno-associated virus antibody profiles in newborns, children, and adolescents. Clin Vaccine Immunol 18:1586–1588
38. Cantore A, Ranzani M, Bartholomae CC et al (2015) Liver-directed lentiviral gene therapy in a dog model of hemophilia B. Sci Transl Med 7:277ra228
39. Cartier N, Hacein-Bey-Abina S, Bartholomae CC et al (2009) Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science 326:818–823
40. Cassiday L (2014) Medical research: Gene-therapy reboot. Nature 509:651–653
41. Castello R, Borzone R, D’Aria S, Annunziata P, Piccolo P, Brunetti-Pierri N (2016) Helper-dependent adenoviral vectors for liver-directed gene therapy of primary hyperoxaluria type 1. Gene Ther 23:129–134
42. Cavazzana-Calvo M, Hacein-Bey S, de Saint BG et al (2000) Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 288:669–672
43. Cerreto M, Mehdawy B, Ombrone D et al (2012) Reversal of metabolic and neurological symptoms of phenylketonuric mice treated with a PAH containing helper-dependent adenoviral vector. Curr Gene Ther 12:48–56
44. Chandler RJ, Venditti CP (2016) Gene therapy for metabolic diseases. Transl Sci Rare Dis 1:73–89
45. Chandler RJ, LaFave MC, Varshney GK et al (2015) Vector design influences hepatic genotoxicity after adeno-associated virus gene therapy. J Clin Invest 125:870–880
46. Chandler RJ, Sands MS, Venditti CP (2017) rAAV integration and genotoxicity: insights from animal models. Hum Gene Ther 28:314–322
47. Chang AH, Stephan MT, Lisowski L, Sadelain M (2008) Erythroid-specific human factor IX delivery from in vivo selected hematopoietic stem cells following nonmyeloablative conditioning in hemophilia B mice. Mol Ther 16:1745–1752
48. Chen Y, Schroeder JA, Kuether EL, Zhang G, Shi Q (2014) Platelet gene therapy by lentiviral gene delivery to hematopoietic stem cells restores hemostasis and induces humoral immune tolerance in FIX(null) mice. Mol Ther 22:169–177
49. Chicoine LG, Montgomery CL, Bremer WG et al (2014) Plasmapheresis eliminates the negative impact of AAV antibodies on microdystrophin gene expression following vascular delivery. Mol Ther 22:338–347
50. Chira S, Jackson CS, Oprea I et al (2015) Progresses towards safe and efficient gene therapy vectors. Oncotarget 6:30675–30703
51. Choudhury SR, Fitzpatrick Z, Harris AF et al (2016) In vivo selection yields AAV-B1 capsid for central nervous system and muscle Gene therapy. Mol Ther 24:1247–1257
52. Chuah MK, Collen D, VandenDriessche T (2004) Clinical gene transfer studies for hemophilia a. Semin Thromb Hemost 30:249–256
53. Cideciyan AV, Aleman TS, Boye SL et al (2008) Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc Natl Acad Sci USA 105:15112–15117
54. Clayton PT (2002) Inborn errors presenting with liver dysfunction. Semin Neonatol 7:49–63
55. Clement N, Grieger JC (2016) Manufacturing of recombinant adeno-associated viral vectors for clinical trials. Mol Ther Methods Clin Dev 3:16002
56. Condiotti R, Goldenberg D, Giladi H et al (2014) Transduction of fetal mice with a feline lentiviral vector induces liver tumors which exhibit an E2F activation signature. Mol Ther 22:59–68
57. Cooper M, Nayak S, Hoffman BE, Terhorst C, Cao O, Herzog RW (2009) Improved induction of immune tolerance to factor IX by hepatic AAV-8 gene transfer. Hum Gene Ther 20:767–776
58. Coppoletta JM, Wolbach SB (1933) Body length and organ weights of infants and children: a study of the Body length and normal weights of the more important vital organs of the Body between birth and twelve years of age. Am J Pathol 9:55–70
59. Corti M, Elder M, Falk D et al (2014) B-cell depletion is protective against anti-AAV capsid immune response: a human subject case study. Mol Ther Methods Clin Dev 1:14033
60. Counsell JR, Asgarian Z, Meng J, Ferrer V, Vink CA, Howe SJ, Waddington SN, Thrasher AJ, Muntoni F, Morgan JE, Danos O (2017) Lentiviral vectors can be used for full-length dystrophin gene therapy. Sci Rep 7:79
61. Couto L, Parker A, Gordon JW (2004) Direct exposure of mouse spermatozoa to very high concentrations of a serotype-2 adeno-associated virus gene therapy vector fails to lead to germ cell transduction. Hum Gene Ther 15:287–291
62. Crane B, Luo X, Demaster A et al (2012) Rescue administration of a helper-dependent adenovirus vector with long-term efficacy in dogs with glycogen storage disease type Ia. Gene Ther 19:443–452
63. Cunningham SC, Dane AP, Spinoulas A, Logan GJ, Alexander IE (2008) Gene delivery to the juvenile mouse liver using AAV2/8 vectors. Mol Ther 16:1081–1088
64. Cunningham SC, Kok CY, Dane AP et al (2011) Induction and prevention of severe hyperammonemia in the spfash mouse model of ornithine transcarbamylase deficiency using shRNA and rAAV-mediated gene delivery. Mol Ther 19:854–859
65. Cunningham SC, Siew SM, Hallwirth CV et al (2015) Modeling correction of severe urea cycle defects in the growing murine liver using a hybrid recombinant adeno-associated virus/piggyBac transposase gene delivery system. Hepatology 62:417–428
66. D’Avola D, Lopez-Franco E, Sangro B et al (2016) Phase I open label liver-directed gene therapy clinical trial for acute intermittent porphyria. J Hepatol 65:776–783
67. Deverman BE, Pravdo PL, Simpson BP et al (2016) Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain. Nat Biotechnol 34:204–209
68. Dhawan A, Mitry RR, Hughes RD (2006) Hepatocyte transplantation for liver-based metabolic disorders. J Inherit Metab Dis 29:431–435
69. Doenecke A, Kromer A, Scherer MN, Schlitt HJ, Geissler EK (2010) AAV plasmid DNA simplifies liver-directed in vivo gene therapy: comparison of expression levels after plasmid DNA-, adeno-associated virus- and adenovirus-mediated liver transfection. J Gene Med 12:810–817
70. Dolgin E (2016) Early clinical data raise the bar for hemophilia gene therapies. Nat Biotechnol 34:999–1001
71. Donsante A, Miller DG, Li Y et al (2007) AAV vector integration sites in mouse hepatocellular carcinoma. Science 317:477
72. Duan D, Yue Y, Engelhardt JF (2001) Expanding AAV packaging capacity with trans-splicing or overlapping vectors: a quantitative comparison. Mol Ther 4:383–391
73. Earley LF, Powers JM, Adachi K et al (2017) Adeno-associated virus (AAV) assembly-activating protein is not an essential requirement for capsid assembly of AAV serotypes 4, 5, and 11. J Virol 91:e01980-16
74. Ehrhardt A, Kay MA (2002) A new adenoviral helper-dependent vector results in long-term therapeutic levels of human coagulation factor IX at low doses in vivo. Blood 99:3923–3930
75. Ehrhardt A, Xu H, Dillow AM, Bellinger DA, Nichols TC, Kay MA (2003) A gene-deleted adenoviral vector results in phenotypic correction of canine hemophilia B without liver toxicity or thrombocytopenia. Blood 102:2403–2411
76. Elsabahy M, Nazarali A, Foldvari M (2011) Non-viral nucleic acid delivery: key challenges and future directions. Curr Drug Deliv 8:235–244
77. Fahs SA, Hille MT, Shi Q, Weiler H, Montgomery RR (2014) A conditional knockout mouse model reveals endothelial cells as the principal and possibly exclusive source of plasma factor VIII. Blood 123:3706–3713
78. Fischer A, Hacein-Bey-Abina S, Cavazzana-Calvo M (2010) 20 years of gene therapy for SCID. Nat Immunol 11:457–460
79. Flanigan KM, Campbell K, Viollet L et al (2013) Anti-dystrophin T cell responses in Duchenne muscular dystrophy: prevalence and a glucocorticoid treatment effect. Hum Gene Ther 24:797–806
80. Flotte TR, Brantly ML, Spencer LT et al (2004) Phase I trial of intramuscular injection of a recombinant adeno-associated virus alpha 1-antitrypsin (rAAV2-CB-hAAT) gene vector to AAT-deficient adults. Hum Gene Ther 15:93–128
81. Flotte TR, Trapnell BC, Humphries M et al (2011) Phase 2 clinical trial of a recombinant adeno-associated viral vector expressing alpha1-antitrypsin: interim results. Hum Gene Ther 22:1239–1247
82. Fumoto S, Kawakami S, Hashida M, Nishida K (2013) Targeted gene delivery: importance of administration routes. In: Good D, Wei M (eds.) Novel gene therapy approaches. doi: 10.5772/54741
83. Gao GP, Yang Y, Wilson JM (1996) Biology of adenovirus vectors with E1 and E4 deletions for liver-directed gene therapy. J Virol 70:8934–8943
84. Gebhardt R, Matz-Soja M (2014) Liver zonation: novel aspects of its regulation and its impact on homeostasis. World J Gastroenterol 20:8491–8504
85. George L, Sullivan S, Giermasz A (2016) Adeno-associated virus mediated gene transfer for Hemophilia B achieves sustained mean factor IX activity levels of >30% without immunosuppression. 58th annual meeting of the American Society of Hemophilia
86. Gil-Farina I, Schmidt M (2016) Interaction of vectors and parental viruses with the host genome. Curr Opin Virol 21:35–40
87. Ginn SL, Alexander IE, Edelstein ML, Abedi MR, Wixon J (2013) Gene therapy clinical trials worldwide to 2012 - an update. J Gene Med 15:65–77
88. Gramignoli R, Vosough M, Kannisto K, Srinivasan RC, Strom SC (2015) Clinical hepatocyte transplantation: practical limits and possible solutions. Eur Surg Res 54:162–177
89. Grieger JC, Soltys SM, Samulski RJ (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 24:287–297
90. Grossman M, Raper SE, Kozarsky K et al (1994) Successful ex vivo gene therapy directed to liver in a patient with familial hypercholesterolaemia. Nat Genet 6:335–341
91. Grossman M, Rader DJ, Muller DW et al (1995) A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolaemia. Nat Med 1:1148–1154
92. Haberle J, Boddaert N, Burlina A et al (2012) Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet Journal of Rare Diseases 7:32
93. Hacein-Bey-Abina S, von Kalle C, Schmidt M et al (2003a) A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 348:255–256
94. Hacein-Bey-Abina S, Von Kalle C, Schmidt M et al (2003b) LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302:415–419
95. Hastie E, Samulski RJ (2015) Recombinant adeno-associated virus vectors in the treatment of rare diseases. Expert Opin Orphan Drugs 3:675–689
96. Herzog RW, Hagstrom JN, Kung SH et al (1997) Stable gene transfer and expression of human blood coagulation factor IX after intramuscular injection of recombinant adeno-associated virus. Proc Natl Acad Sci USA 94:5804–5809
97. Herzog RW, Yang EY, Couto LB et al (1999) Long-term correction of canine hemophilia B by gene transfer of blood coagulation factor IX mediated by adeno-associated viral vector. Nat Med 5:56–63
98. Hickey RD, Mao SA, Glorioso J et al (2016) Curative ex vivo liver-directed gene therapy in a pig model of hereditary tyrosinemia type 1. Sci Transl Med 8:349ra399
99. Hirsch ML, Wolf SJ, Samulski RJ (2016) Delivering transgenic DNA exceeding the carrying capacity of AAV vectors. Methods Mol Biol 1382:21–39
100. Hoggatt J (2016) Gene therapy for "bubble boy" disease. Cell 166:263
101. Hou X, Jiao R, Guo X et al (2016) Construction of minicircle DNA vectors capable of correcting familial hypercholesterolemia phenotype in a LDLR-deficient mouse model. Gene Ther 23:657–663
102. Hu C, Cela RG, Suzuki M, Lee B, Lipshutz GS (2011) Neonatal helper-dependent adenoviral vector gene therapy mediates correction of hemophilia a and tolerance to human factor VIII. Proc Natl Acad Sci USA 108:2082–2087
103. Jayandharan GR, Aslanidi G, Martino AT et al (2011) Activation of the NF-kappaB pathway by adeno-associated virus (AAV) vectors and its implications in immune response and gene therapy. Proc Natl Acad Sci USA 108:3743–3748
104. Jiang H, Couto LB, Patarroyo-White S et al (2006a) Effects of transient immunosuppression on adenoassociated, virus-mediated, liver-directed gene transfer in rhesus macaques and implications for human gene therapy. Blood 108:3321–3328
105. Jiang H, Pierce GF, Ozelo MC et al (2006b) Evidence of multiyear factor IX expression by AAV-mediated gene transfer to skeletal muscle in an individual with severe hemophilia B. Mol Ther 14:452–455
106. Jooss K, Chirmule N (2003) Immunity to adenovirus and adeno-associated viral vectors: implications for gene therapy. Gene Ther 10:955–963
107. Junge N, Mingozzi F, Ott M, Baumann U (2015) Adeno-associated virus vector-based gene therapy for monogenetic metabolic diseases of the liver. J Pediatr Gastroenterol Nutr 60:433–440
108. Kaeppel C, Beattie SG, Fronza R et al (2013) A largely random AAV integration profile after LPLD gene therapy. Nat Med 19:889–891
109. Kalyuzhniy O, Di Paolo NC, Silvestry M et al (2008) Adenovirus serotype 5 hexon is critical for virus infection of hepatocytes in vivo. Proc Natl Acad Sci USA 105:5483–5488
110. Kattenhorn LM, Tipper CH, Stoica L et al (2016) Adeno-associated virus Gene therapy for liver disease. Hum Gene Ther 27:947–961
111. Kay MA (2011) State-of-the-art gene-based therapies: the road ahead. Nat Rev Genet 12:316–328
112. Kay MA, Manno CS, Ragni MV et al (2000) Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector. Nat Genet 24:257–261
113. Kay MA, He CY, Chen ZY (2010) A robust system for production of minicircle DNA vectors. Nat Biotechnol 28:1287–1289
114. Kiang A, Hartman ZC, Everett RS et al (2006) Multiple innate inflammatory responses induced after systemic adenovirus vector delivery depend on a functional complement system. Mol Ther 14:588–598
115. Kim IH, Jozkowicz A, Piedra PA, Oka K, Chan L (2001) Lifetime correction of genetic deficiency in mice with a single injection of helper-dependent adenoviral vector. Proc Natl Acad Sci USA 98:13282–13287
116. Koeberl DD, Sun B, Bird A, Chen YT, Oka K, Chan L (2007) Efficacy of helper-dependent adenovirus vector-mediated gene therapy in murine glycogen storage disease type Ia. Mol Ther 15:1253–1258
117. Koo T, Popplewell L, Athanasopoulos T, Dickson G (2014) Triple trans-splicing adeno-associated virus vectors capable of transferring the coding sequence for full-length dystrophin protein into dystrophic mice. Hum Gene Ther 25:98–108
118. Kotterman MA, Schaffer DV (2014) Engineering adeno-associated viruses for clinical gene therapy. Nat Rev Genet 15:445–451
119. Kotterman MA, Chalberg TW, Schaffer DV (2015) Viral vectors for gene therapy: translational and clinical outlook. Annu Rev Biomed Eng 17:63–89
120. Kuether EL, Schroeder JA, Fahs SA et al (2012) Lentivirus-mediated platelet gene therapy of murine hemophilia a with pre-existing anti-factor VIII immunity. J Thromb Haemost 10:1570–1580
121. Ledley FD, McNamee LM, Uzdil V, Morgan IW (2014) Why commercialization of gene therapy stalled; examining the life cycles of gene therapy technologies. Gene Ther 21:188–194
122. Li C, Narkbunnam N, Samulski RJ et al (2012) Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia. Gene Ther 19:288–294
123. Li M, Dick A, Montenovo M, Horslen S, Hansen R (2015) Cost-effectiveness of liver transplantation in methylmalonic and propionic acidemias. Liver Transpl 21:1208–1218
124. Lipshutz GS, Titre D, Brindle M, Bisconte AR, Contag CH, Gaensler KM (2003) Comparison of gene expression after intraperitoneal delivery of AAV2 or AAV5 in utero. Mol Ther 8:90–98
125. Lisowski L, Dane AP, Chu K et al (2014) Selection and evaluation of clinically relevant AAV variants in a xenograft liver model. Nature 506:382–386
126. Liu F, Song Y, Liu D (1999) Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA. Gene Ther 6:1258–1266
127. Louis Jeune V, Joergensen JA, Hajjar RJ, Weber T (2013) Pre-existing anti-adeno-associated virus antibodies as a challenge in AAV gene therapy. Hum Gene Ther Methods 24:59–67
128. Lozier JN, Metzger ME, Donahue RE, Morgan RA (1999) Adenovirus-mediated expression of human coagulation factor IX in the rhesus macaque is associated with dose-limiting toxicity. Blood 94:3968–3975
129. Lu J, Williams JA, Luke J, Zhang F, Chu K, Kay MA (2017) A 5′ noncoding exon containing engineered intron enhances transgene expression from recombinant AAV vectors in vivo. Hum Gene Ther 28:125–134
130. Macaulay R (2015) How ready are european payers for ema adaptive pathways? Value Health 18:A341
131. Maguire AM, Simonelli F, Pierce EA et al (2008) Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med 358:2240–2248
132. Mah C, Sarkar R, Zolotukhin I et al (2003) Dual vectors expressing murine factor VIII result in sustained correction of hemophilia a mice. Hum Gene Ther 14:143–152
133. Majhen D, Calderon H, Chandra N et al (2014) Adenovirus-based vaccines for fighting infectious diseases and cancer: progress in the field. Hum Gene Ther 25:301–317
134. Manno CS, Chew AJ, Hutchison S et al (2003) AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood 101:2963–2972
135. Manno CS, Pierce GF, Arruda VR et al (2006) Successful transduction of liver in hemophilia by AAV-factor IX and limitations imposed by the host immune response. Nat Med 12:342–347
136. Mattar CN, Nathwani AC, Waddington SN et al (2011) Stable human FIX expression after 0.9G intrauterine gene transfer of self-complementary adeno-associated viral vector 5 and 8 in macaques. Mol Ther 19:1950–1960
137. Mayrhofer P, Schleef M, Jechlinger W (2009) Use of minicircle plasmids for gene therapy. Methods Mol Biol 542:87–104
138. McCarty DM (2008) Self-complementary AAV vectors; advances and applications. Mol Ther 16:1648–1656
139. McCarty DM, Young SM Jr, Samulski RJ (2004) Integration of adeno-associated virus (AAV) and recombinant AAV vectors. Annu Rev Genet 38:819–845
140. McCormack WM Jr, Seiler MP, Bertin TK et al (2006) Helper-dependent adenoviral gene therapy mediates long-term correction of the clotting defect in the canine hemophilia a model. J Thromb Haemost 4:1218–1225
141. McGarrity GJ, Hoyah G, Winemiller A et al (2013) Patient monitoring and follow-up in lentiviral clinical trials. J Gene Med 15:78–82
142. McIntosh JH, Cochrane M, Cobbold S et al (2012) Successful attenuation of humoral immunity to viral capsid and transgenic protein following AAV-mediated gene transfer with a non-depleting CD4 antibody and cyclosporine. Gene Ther 19:78–85
143. McKay TR, Rahim AA, Buckley SM et al (2011) Perinatal gene transfer to the liver. Curr Pharm Des 17:2528–2541
144. Mian A, Lee B (2002) Urea-cycle disorders as a paradigm for inborn errors of hepatocyte metabolism. Trends Mol Med 8:583–589
145. Miesbach W, Tangelder M, Klamroth R (2016) Updated results from a dose escalating study in adult patients with haemophilia B treated with AMT-060 (AAV5-hFIX) gene therapy. Haemophilia 22:151
146. Miller DG, Adam MA, Miller AD (1990) Gene transfer by retrovirus vectors occurs only in cells that are actively replicating at the time of infection. Mol Cell Biol 10:4239–4242
147. Mingozzi F, High KA (2007) Immune responses to AAV in clinical trials. Curr Gene Ther 7:316–324
148. Mingozzi F, High KA (2011) Immune responses to AAV in clinical trials. Curr Gene Ther 11:321–330
149. Mingozzi F, High KA (2013) Immune responses to AAV vectors: overcoming barriers to successful gene therapy. Blood 122:23–36
150. Mingozzi F, Maus MV, Hui DJ et al (2007) CD8(+) T-cell responses to adeno-associated virus capsid in humans. Nat Med 13:419–422
151. Mingozzi F, Chen Y, Murphy SL et al (2012) Pharmacological modulation of humoral immunity in a nonhuman primate model of AAV gene transfer for hemophilia B. Mol Ther 20:1410–1416
152. Mingozzi F, Chen Y, Edmonson SC et al (2013) Prevalence and pharmacological modulation of humoral immunity to AAV vectors in gene transfer to synovial tissue. Gene Ther 20:417–424
153. Miyoshi H, Blomer U, Takahashi M, Gage FH, Verma IM (1998) Development of a self-inactivating lentivirus vector. J Virol 72:8150–8157
154. Monahan PE, Lothrop CD, Sun J et al (2010) 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 18:1907–1916
155. Monahan P, Walsh C, Powell J (2015) 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 13(Suppl 2):87
156. Monteilhet V, Saheb S, Boutin S 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 19:2084–2091
157. Morral N, O’Neal W, Rice K et al (1999) Administration of helper-dependent adenoviral vectors and sequential delivery of different vector serotype for long-term liver-directed gene transfer in baboons. Proc Natl Acad Sci USA 96:12816–12821
158. Morral N, O’Neal WK, Rice K et al (2002) Lethal toxicity, severe endothelial injury, and a threshold effect with high doses of an adenoviral vector in baboons. Hum Gene Ther 13:143–154
159. Mukherjee S, Thrasher AJ (2013) Gene therapy for PIDs: progress, pitfalls and prospects. Gene 525:174–181
160. Mullard A (2016) European regulators launch "breakthrough" equivalent programme. Nat Rev Drug Discov 15:223
161. Muruve DA, Cotter MJ, Zaiss AK et al (2004) Helper-dependent adenovirus vectors elicit intact innate but attenuated adaptive host immune responses in vivo. J Virol 78:5966–5972
162. Narayanan G, Cossu G, Galli MC et al (2014) Clinical development of gene therapy needs a tailored approach: a regulatory perspective from the European Union. Hum Gene Ther Clin Dev 25:1–6
163. Nathwani AC, Gray JT, McIntosh J et al (2007) 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 109:1414–1421
164. Nathwani AC, Rosales C, McIntosh J et al (2011) Long-term safety and efficacy following systemic administration of a self-complementary AAV vector encoding human FIX pseudotyped with serotype 5 and 8 capsid proteins. Mol Ther 19:876–885
165. Nathwani AC, Reiss UM, Tuddenham EG et al (2014) Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med 371:1994–2004
166. Nault JC, Datta S, Imbeaud S et al (2015) Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas. Nat Genet 47:1187–1193
167. Naumer M, Sonntag F, Schmidt K et al (2012) Properties of the adeno-associated virus assembly-activating protein. J Virol 86:13038–13048
168. Nguyen TH, Mainot S, Lainas P et al (2009) Ex vivo liver-directed gene therapy for the treatment of metabolic diseases: advances in hepatocyte transplantation and retroviral vectors. Curr Gene Ther 9:136–149
169. Nienhuis AW, Nathwani AC, Davidoff AM (2016) Gene therapy for hemophilia. Hum Gene Ther 27:305–308
170. Nightingale SJ, Hollis RP, Pepper KA et al (2006) Transient gene expression by nonintegrating lentiviral vectors. Mol Ther 13:1121–1132
171. Nomura S, Merched A, Nour E, Dieker C, Oka K, Chan L (2004) Low-density lipoprotein receptor gene therapy using helper-dependent adenovirus produces long-term protection against atherosclerosis in a mouse model of familial hypercholesterolemia. Gene Ther 11:1540–1548
172. Nowrouzi A, Cheung WT, Li T et al (2013) The fetal mouse is a sensitive genotoxicity model that exposes lentiviral-associated mutagenesis resulting in liver oncogenesis. Mol Ther 21:324–337
173. Oishi Y, Kakimoto T, Yuan W, Kuno S, Yamashita H, Chiba T (2016) Fetal Gene therapy for ornithine Transcarbamylase deficiency by intrahepatic plasmid DNA-micro-bubble injection combined with hepatic ultrasound Insonation. Ultrasound Med Biol 42:1357–1361
174. Orkin SH, Motulsky AG (1995) Report and recommendations of the panel to assess the NIH investment in research on gene therapy. National Institute of Health, Bethesda
175. Orkin SH, Reilly P (2016) MEDICINE. Paying for future success in gene therapy. Science 352:1059–1061
176. Pasi J, Wong W, Rangarajan S (2016) Interim results of an open-label, phase 1/2 study of BMN 270, an AAV5-FVIII gene transfer in severe hemophilia a. Haemophilia 22:151
177. Perrin GQ, Zolotukhin I, Sherman A et al (2016) 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 3:16083
178. Philippe S, Sarkis C, Barkats M et al (2006) Lentiviral vectors with a defective integrase allow efficient and sustained transgene expression in vitro and in vivo. Proc Natl Acad Sci USA 103:17684–17689
179. Piccolo P, Brunetti-Pierri N (2014) Challenges and prospects for helper-dependent adenoviral vector-mediated gene therapy. Biomedicine 2:132–148
180. Pien GC, Basner-Tschakarjan E, Hui DJ et al (2009) Capsid antigen presentation flags human hepatocytes for destruction after transduction by adeno-associated viral vectors. J Clin Invest 119:1688–1695
181. Pillay S, Meyer NL, Puschnik AS et al (2016) An essential receptor for adeno-associated virus infection. Nature 530:108–112
182. Powell JS, Ragni MV, White GC 2nd et al (2003) Phase 1 trial of FVIII gene transfer for severe hemophilia a using a retroviral construct administered by peripheral intravenous infusion. Blood 102:2038–2045
183. Puumalainen AM, Vapalahti M, Agrawal RS et al (1998) Beta-galactosidase gene transfer to human malignant glioma in vivo using replication-deficient retroviruses and adenoviruses. Hum Gene Ther 9:1769–1774
184. Rabinowitz JE, Rolling F, Li C et al (2002) Cross-packaging of a single adeno-associated virus (AAV) type 2 vector genome into multiple AAV serotypes enables transduction with broad specificity. J Virol 76:791–801
185. Rahim AA, Wong AM, Howe SJ et al (2009) Efficient gene delivery to the adult and fetal CNS using pseudotyped non-integrating lentiviral vectors. Gene Ther 16:509–520
186. Raper SE, Grossman M, Rader DJ et al (1996) Safety and feasibility of liver-directed ex vivo gene therapy for homozygous familial hypercholesterolemia. Ann Surg 223:116–126
187. Raper SE, Haskal ZJ, Ye X et al (1998) Selective gene transfer into the liver of non-human primates with E1-deleted, E2A-defective, or E1-E4 deleted recombinant adenoviruses. Hum Gene Ther 9:671–679
188. Raper SE, Yudkoff M, Chirmule N et al (2002) A pilot study of in vivo liver-directed gene transfer with an adenoviral vector in partial ornithine transcarbamylase deficiency. Hum Gene Ther 13:163–175
189. Raper SE, Chirmule N, Lee FS et al (2003) Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab 80:148–158
190. Rastall DP, Seregin SS, Aldhamen YA et al (2016) Long-term, high-level hepatic secretion of acid alpha-glucosidase for Pompe disease achieved in non-human primates using helper-dependent adenovirus. Gene Ther 23:743–752
191. Reddy PS, Sakhuja K, Ganesh S et al (2002) Sustained human factor VIII expression in hemophilia a mice following systemic delivery of a gutless adenoviral vector. Mol Ther 5:63–73
192. Rosewell Shaw A, Suzuki M (2016) Recent advances in oncolytic adenovirus therapies for cancer. Curr Opin Virol 21:9–15
193. Samulski RJ, Muzyczka N (2014) AAV-mediated gene therapy for research and therapeutic purposes. Annu Rev Virol 1:427–451
194. Sarkar R, Mucci M, Addya S et al (2006) Long-term efficacy of adeno-associated virus serotypes 8 and 9 in hemophilia a dogs and mice. Hum Gene Ther 17:427–439
195. Schiedner G, Bloch W, Hertel S et al (2003) A hemodynamic response to intravenous adenovirus vector particles is caused by systemic Kupffer cell-mediated activation of endothelial cells. Hum Gene Ther 14:1631–1641
196. Schimmer J, Breazzano S (2016) Investor outlook: solving gene therapy pricing..with a cures voucher? Hum Gene Ther Clin Dev 27:132–136
197. Schmitt F, Pastore N, Abarrategui-Pontes C et al (2014) Correction of hyperbilirubinemia in gunn rats by surgical delivery of low doses of helper-dependent adenoviral vectors. Hum Gene Ther Methods 25:181–186
198. Sendra L, Miguel A, Perez-Enguix D et al (2016) Studying closed hydrodynamic models of "in vivo" DNA perfusion in pig liver for Gene therapy translation to humans. PLoS One 11:e0163898
199. Shi Y, Falahati R, Zhang J, Flebbe-Rehwaldt L, Gaensler KM (2013) Role of antigen-specific regulatory CD4+CD25+ T cells in tolerance induction after neonatal IP administration of AAV-hF.IX. Gene Ther 20:987–996
200. Sokal EM (2006) Liver transplantation for inborn errors of liver metabolism. J Inherit Metab Dis 29:426–430
201. Spada M, Riva S, Maggiore G, Cintorino D, Gridelli B (2009) Pediatric liver transplantation. World J Gastroenterol 15:648–674
202. Stephen SL, Montini E, Sivanandam VG et al (2010) Chromosomal integration of adenoviral vector DNA in vivo. J Virol 84:9987–9994
203. Summerford C, Samulski RJ (2016) AAVR: a multi-serotype receptor for AAV. Mol Ther 24:663–666
204. Sunderman FW, Boerner F (1949) Normal value in clinical medicine. Saunders, Philadelphia
205. Suwanmanee T, Hu G, Gui T et al (2014) Integration-deficient lentiviral vectors expressing codon-optimized R338L human FIX restore normal hemostasis in hemophilia B mice. Mol Ther 22:567–574
206. Suzuki T, Sasaki T, Yano K et al (2011) Development of a recombinant adenovirus vector production system free of replication-competent adenovirus by utilizing a packaging size limit of the viral genome. Virus Res 158:154–160
207. Suzuki M, Bertin TK, Rogers GL et al (2013) Differential type I interferon-dependent transgene silencing of helper-dependent adenoviral vs. adeno-associated viral vectors in vivo. Mol Ther 21:796–805
208. Tang J, Olive M, Pulmanausahakul R et al (2006) Human CD8+ cytotoxic T cell responses to adenovirus capsid proteins. Virology 350:312–322
209. Thaci B, Ulasov IV, Wainwright DA, Lesniak MS (2011) The challenge for gene therapy: innate immune response to adenoviruses. Oncotarget 2:113–121
210. Thwaite R, Pages G, Chillon M, Bosch A (2015) AAVrh.10 immunogenicity in mice and humans. Relevance of antibody cross-reactivity in human gene therapy. Gene Ther 22:196–201
211. Toietta G, Mane VP, Norona WS et al (2005) Lifelong elimination of hyperbilirubinemia in the Gunn rat with a single injection of helper-dependent adenoviral vector. Proc Natl Acad Sci USA 102:3930–3935
212. Touchot N, Flume M (2015) The payers’ perspective on gene therapies. Nat Biotechnol 33:902–904
213. Trapani I, Colella P, Sommella A et al (2014) Effective delivery of large genes to the retina by dual AAV vectors. EMBO Mol Med 6:194–211
214. Tse LV, Moller-Tank S, Asokan A (2015) Strategies to circumvent humoral immunity to adeno-associated viral vectors. Expert Opin Biol Ther 15:845–855
215. Tseng YS, Agbandje-McKenna M (2014) Mapping the AAV capsid host antibody response toward the development of second generation Gene delivery vectors. Front Immunol 5:9
216. Unzu C, Sampedro A, Mauleon I et al (2013) Helper-dependent adenoviral liver gene therapy protects against induced attacks and corrects protein folding stress in acute intermittent porphyria mice. Hum Mol Genet 22:2929–2940
217. Vercauteren K, Hoffman BE, Zolotukhin I et al (2016) Superior in vivo transduction of human hepatocytes using engineered AAV3 capsid. Mol Ther 24:1042–1049
218. Verma IM, Somia N (1997) Gene therapy - promises, problems and prospects. Nature 389:239–242
219. Viecelli HM, Harbottle RP, Wong SP et al (2014) Treatment of phenylketonuria using minicircle-based naked-DNA gene transfer to murine liver. Hepatology 60:1035–1043
220. Vigant F, Descamps D, Jullienne B et al (2008) Substitution of hexon hypervariable region 5 of adenovirus serotype 5 abrogates blood factor binding and limits gene transfer to liver. Mol Ther 16:1474–1480
221. Waddington SN, McVey JH, Bhella D et al (2008) Adenovirus serotype 5 hexon mediates liver gene transfer. Cell 132:397–409
222. Wang L, Bell P, Somanathan S et al (2015) Comparative study of liver Gene transfer with AAV vectors based on natural and engineered AAV capsids. Mol Ther 23:1877–1887
223. White GI, Monahan PE (2005) Gene therapy for hemophilia a. In: Lee CR, Berntrop E, Hoots K (eds) Textbook of hemophilia. Blackwell, Oxford, pp 226–228
224. Wilson JM (2009) Lessons learned from the gene therapy trial for ornithine transcarbamylase deficiency. Mol Genet Metab 96:151–157
225. Wilson EM, Bial J, Tarlow B et al (2014) Extensive double humanization of both liver and hematopoiesis in FRGN mice. Stem Cell Res 13:404–412
226. Wirth T, Parker N, Yla-Herttuala S (2013) History of gene therapy. Gene 525:162–169
227. Wold WS, Toth K (2013) Adenovirus vectors for gene therapy, vaccination and cancer gene therapy. Curr Gene Ther 13:421–433
228. Wolff JA, Budker V (2005) The mechanism of naked DNA uptake and expression. Adv Genet 54:3–20
229. Wu X, Liu G, Mu M et al (2016) Augmenter of liver regeneration gene therapy using a novel minicircle DNA vector alleviates liver fibrosis in rats. Hum Gene Ther 27:880–891
230. Yan Z, Sun X, Feng Z et al (2015) Optimization of recombinant adeno-associated virus-mediated expression for large transgenes, using a synthetic promoter and tandem array enhancers. Hum Gene Ther 26:334–346
231. Yanez-Munoz RJ, Balaggan KS, MacNeil A et al (2006) Effective gene therapy with nonintegrating lentiviral vectors. Nat Med 12:348–353
232. Yang Y, Ertl HC, Wilson JM (1994) MHC class I-restricted cytotoxic T lymphocytes to viral antigens destroy hepatocytes in mice infected with E1-deleted recombinant adenoviruses. Immunity 1:433–442
233. Yang Y, Wang L, Bell P et al (2016) A dual AAV system enables the Cas9-mediated correction of a metabolic liver disease in newborn mice. Nat Biotechnol 34:334–338
234. Yokoo T, Kamimura K, Abe H et al (2016) Liver-targeted hydrodynamic gene therapy: recent advances in the technique. World J Gastroenterol 22:8862–8868
235. Zaiss AK, Muruve DA (2008) Immunity to adeno-associated virus vectors in animals and humans: a continued challenge. Gene Ther 15:808–816
236. Zhang HG, Zhou T, Yang P, Edwards CK 3rd, Curiel DT, Mountz JD (1998) Inhibition of tumor necrosis factor alpha decreases inflammation and prolongs adenovirus gene expression in lung and liver. Hum Gene Ther 9:1875–1884
237. Zhu J, Huang X, Yang Y (2007) Innate immune response to adenoviral vectors is mediated by both Toll-like receptor-dependent and -independent pathways. J Virol 81:3170–3180
238. Zufferey R, Dull T, Mandel RJ et al (1998) Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery. J Virol 72:9873–9880