Therapeutic in vivo gene transfer for genetic disease using AAV: Progress and challenges

Nature Reviews Genetics

Volumn 12, Issue 5, 2011, Pages 341-355

  Mingozzi, Federico ^a   High, Katherine A ^a,b  

^a CHILDREN S HOSPITAL OF PHILADELPHIA   (United States)

^b UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA 1 ANTITRYPSIN; ALPHA SARCOGLYCAN; ASPARTOACYLASE; BLOOD CLOTTING FACTOR 9; GLUCURONOSYLTRANSFERASE 1A1; PHENYLALANINE;

ADENO ASSOCIATED VIRUS; CONGENITAL DISORDER; GENE EXPRESSION; GENE SILENCING; GENETIC DISORDER; HEMOPHILIA B; HUMAN; IMMUNE RESPONSE; IMMUNOTOXICITY; IN VIVO GENE TRANSFER; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; RETINA DISEASE; REVIEW; TRANSGENICS;

ANIMALS; CLINICAL TRIALS AS TOPIC; DEPENDOVIRUS; DOGS; GENE THERAPY; GENE TRANSFER TECHNIQUES; GENETIC DISEASES, INBORN; GENETIC VECTORS; HEMOPHILIA B; HUMANS; MALE; MICE; RATS; RETINAL DISEASES;

ADENO-ASSOCIATED VIRUS; ANIMALIA;

EID: 79954622209     PISSN: 14710056     EISSN: 14710064     Source Type: Journal    
DOI: 10.1038/nrg2988     Document Type: Review

References (176)

1. McCandless, S. E., Brunger, J. W. & Cassidy, S. B. The burden of genetic disease on inpatient care in a children's hospital. Am. J. Hum. Genet. 74, 121-127 (2004). (Pubitemid 38085243)
2. Emery, A. E. H. & Rimoin, D. L. Principles and Practice of Medical Genetics 2nd edn (Churchill Livingstone, New York, 1990).
3. Aiuti, A. et al. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N. Engl. J. Med. 360, 447-458 (2009).
4. Bainbridge, J. W. et al. Effect of gene therapy on visual function in Leber's congenital amaurosis. N. Engl. J. Med. 358, 2231-2239 (2008). (Pubitemid 351724452)
5. Cartier, N. et al. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy Science 326, 818-823 (2009).
6. Maguire, A. M. et al. Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial. Lancet 374, 1597-1605 (2009).
7. Maguire, A. M. et al. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N. Engl. J. Med. 358, 2240-2248 (2008). (Pubitemid 351724453)
8. Nathwani, A. C. et al. Early clinical trial results following administration of a low dose of a novel self complementary adeno-associated viral vector encoding human Factor IX in two subjects with severe hemophilia B. Blood (ASH Annual Meeting Abstracts) 116, abstract 248 (2010).
9. Ponder, K. P. Hemophilia gene therapy: a holy grail found. Mol. Ther. 19, 427-428 (2011).
10. Kay, M. A. State-of-the-art gene-based therapies: the road ahead. Nature Rev. Genet. 12, 316-328 (2011).
11. Amsterdam Molecular Therapeutics. AMT submits its lead product Glybera® application for marketing authorisation to EMA. Amsterdam Molecular Therapeutics [online], http://www.amtbiopharma.com/uploads/011110e-pdf 44.pdf (2010).
12. Gaudet, D. et al. Review of the clinical development of alipogene tiparvovec gene therapy for lipoprotein lipase deficiency. Atheroscler. Suppl. 11, 55-60 (2010).
13. Naldini, L. Ex vivo gene transfer and correction for cell-based therapies. Nature Rev. Genet. 12, 301-315 (2011).
14. den Hollander, A. I., Roepman, R., Koenekoop, R. K. & Cremers, F. P. Leber congenital amaurosis: genes, proteins and disease mechanisms. Prog. Retin. Eye Res. 27, 391-419 (2008).
15. Jacobson, S. G. et al. Identifying photoreceptors in blind eyes caused by RPE65 mutations: prerequisite for human gene therapy success. Proc. Natl Acad. Sci. USA 102, 6177-6182 (2005). (Pubitemid 40594274)
16. Acland, G. M. et al. Gene therapy restores vision in a canine model of childhood blindness. Nature Genet. 28, 92-95 (2001). (Pubitemid 32405824)
17. Hauswirth, W. W. et al. 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, 979-990 (2008).
18. Cideciyan, A. V. et al. Vision 1 year after gene therapy for Leber's congenital amaurosis. N. Engl. J. Med. 361, 725-727 (2009).
19. Simonelli, F et al. Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration. Mol. Ther. 18, 643-650 (2010).
20. Acland, G. M. et al. Long-term restoration of rod and cone vision by single dose rAAV-mediated gene transfer to the retina in a canine model of childhood blindness. Mol. Ther. 12, 1072-1082 (2005). (Pubitemid 41723041)
21. Hiraki, S. & Green, N. S. Newborn screening for treatable genetic conditions: past, present and future. Obstet. Gynecol. Clin. North Am. 37, 11-21 (2010).
22. Lam, B. L. et al. Leber hereditary optic neuropathy gene therapy clinical trial recruitment: year 1. Arch. Ophthalmol. 128, 1129-1135 (2010).
23. Anand, V. et al. Gene therapy for choroideremia: in vitro rescue mediated by recombinant adenovirus. Vision Res. 43, 919-926 (2003). (Pubitemid 36369132)
24. Moscioni, D. et al. Long-term correction of ammonia metabolism and prolonged survival in ornithine transcarbamylase-deficient mice following liver-directed treatment with adeno-associated viral vectors. Mol. Ther. 14, 25-33 (2006). (Pubitemid 43899486)
25. Carrillo-Carrasco, N., Chandler, R. J., Chandrasekaran, S. & Venditti, C. P. Liver-directed recombinant adeno-associated viral gene delivery rescues a lethal mouse model of methylmalonic acidemia and provides long-term phenotypic correction. Hum. Gene Ther. 21, 1147-1154 (2010).
26. Lofqvist, T., Nilsson, I. M., Berntorp, E. & Pettersson, H. Haemophilia prophylaxis in young patients-a long-term follow-up. J. Intern. Med. 241, 395-400 (1997). (Pubitemid 27244664)
27. Manco-Johnson, M. J. et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N. Engl. J. Med. 357, 535-544 (2007). (Pubitemid 47236278)
28. Evatt, B. L., Black, C, Batorova, A., Street, A. & Srivastava, A. Comprehensive care for haemophilia around the world. Haemophilia 10, 9-13 (2004). (Pubitemid 40045413)
29. Lin, H. F, Maeda, N., Smithies, O., Straight, D. L. & Stafford, D. W. A coagulation factor IX-deficient mouse model for human hemophilia B. Blood 90, 3962-3966 (1997). (Pubitemid 27484049)
30. Wang, L. et al. A factor IX-deficient mouse model for hemophilia B gene therapy. Proc. Natl Acad. Sci. USA 94, 11563-11566 (1997). (Pubitemid 27451038)
31. Yao, S. N. & Kurachi, K. Expression of human factor IX in mice after injection of genetically modified myoblasts. Proc. Natl Acad. Sci. USA 89, 3357-3361 (1992).
32. Bi, L. et al. Targeted disruption of the mouse factor VIII gene produces a model of haemophilia A. Nature Genet. 10, 119-121 (1995).
33. Evans, J. P., Brinkhous, K. M., Brayer, G. D., Reisner, H. M. & High, K. A. Canine hemophilia B resulting from a point mutation with unusual consequences. Proc. Natl Acad. Sci. USA 86, 10095-10099 (1989). (Pubitemid 20030783)
34. Lozier, J. N. et al. Efficient transfection of primary cells in a canine hemophilia B model using adenovirus-polylysine-DNA complexes. Hum. Gene Ther. 5, 313-322 (1994). (Pubitemid 24310542)
35. Mauser, A. E., Whitlark, J., Whitney, K. M. & Lothrop, C. D. Jr. A deletion mutation causes hemophilia B in Lhasa Apso dogs. Blood 88, 3451-3455 (1996). (Pubitemid 26365579)
36. Manno, C. S. et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nature Med. 12, 342-347 (2006). (Pubitemid 43355084)
37. Mount, J. D. et al. Sustained phenotypic correction of hemophilia B dogs with a factor IX null mutation by liver-directed gene therapy. Blood 99, 2670-2676 (2002). (Pubitemid 34525351)
38. Wang, L. et al. Sustained correction of disease in naive and AAV2-pretreated hemophilia B dogs: AAV2/8-mediated, liver-directed gene therapy. Blood 105, 3079-3086 (2005).
39. Manno, C. S. et al. AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood 101, 2963-2972 (2003). (Pubitemid 36857981)
40. Franco, L. M. et al. Evasion of immune responses to introduced human acid α-glucosidase by liver-restricted expression in glycogen storage disease type II. Mol. Ther. 12, 876-884 (2005). (Pubitemid 41614483)
41. Mingozzi, F et al. Induction of immune tolerance to coagulation factor IX antigen by in vivo hepatic gene transfer. J. Clin. Invest. 111, 1347-1356 (2003). (Pubitemid 36554705)
42. Ziegler, R. J. 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. 9, 231-240 (2004). (Pubitemid 38256549)
43. Follenzi, A. et al. 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, 3700-3709 (2004). (Pubitemid 38596285)
44. Xu, L. et al. Immune response after neonatal transfer of a human factor IX-expressing retroviral vector in dogs, cats, and mice. Thromb. Res. 120, 269-280 (2007). (Pubitemid 46754415)
45. Raper, S. E. et al. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol. Genet. Metab. 80, 148-158 (2003). (Pubitemid 37272241)
46. + T-cell responses to adeno-associated virus capsid in humans. Nature Med. 13, 419-422 (2007). (Pubitemid 46559826)
47. Jiang, H. et al. 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 (2006).
48. Mingozzi, F et al. Modulation of tolerance to the transgene product in a nonhuman primate model of AAV-mediated gene transfer to liver. Blood 110, 2334-2341 (2007). (Pubitemid 47523153)
49. Hauck, B. et al. Undetectable transcription of cap in a clinical AAV vector: implications for preformed capsid in immune responses. Mol. Ther. 17, 144-152 (2009)
50. National Institutes of Health Office of Biotechnology Activities. Immune responses to adeno-associated virus (AAV) vectors: NIH Recombinant DNA Advisory Committee Meeting. National Institutes of Health Office of Biotechnology Activities [online], http://oba. od.nih.gov/oba/rac/meetings/jun07/AAV%20 summary%20June%202007f.pdf (2007).
51. Li, C. et al. Cellular immune response to cryptic epitopes during therapeutic gene transfer. Proc. Natl Acad. Sci. USA 106, 10770-10774 (2009).
52. Vandenberghe, L. H. et al. Heparin binding directs activation of T cells against adeno-associated virus serotype 2 capsid. Nature Med. 12, 967-971 (2006). (Pubitemid 44175151)
53. Basner-Tschakarjan, E. et al. Dose-dependent activation of capsid-specific T cells after AAV serotype 8 vector administration in a clinical study for hemophilia. Mol. Ther. (in the press).
54. + T cells are unable to eliminate AAV-transduced hepatocytes. Mol. Ther. 15, 792-800 (2007). (Pubitemid 46432000)
55. Li, C. 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. 81, 7540-7547 (2007). (Pubitemid 47047840)
56. Wang, L, Figueredo, J., Calcedo, R., Lin, J. & Wilson, J. M. 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, 185-194 (2007). (Pubitemid 46626458)
57. Pien, G. C. et al. Capsid antigen presentation flags human hepatocytes for destruction after transduction by adeno-associated viral vectors. J. Clin. Invest. 119, 1688-1695 (2009).
58. Nathwani, A. C. 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 109, 1414-1421 (2007). (Pubitemid 46239572)
59. McCarty, D. M. et al. Adeno-associated virus terminal repeat (TR) mutant generates self-complementary vectors to overcome the rate-limiting step to transduction in vivo. Gene Ther. 10, 2112-2118 (2003). (Pubitemid 37536760)
60. Nathwani, A. C. et al. Self-complementary adeno-associated virus vectors containing a novel liver-specific human factor IX expression cassette enable highly efficient transduction of murine and nonhuman primate liver. Blood 107, 2653-2661 (2006).
61. Calcedo, R., Vandenberghe, L. H., Gao, G., Lin, J. & Wilson, J. M. Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. J. Infect. Dis. 199, 381-390 (2009).
62. Donsante, A. et al. AAV vector integration sites in mouse hepatocellular carcinoma. Science 317, 477 (2007). (Pubitemid 47196106)
63. Li, H. et al. Assessing the potential for AAV vector genotoxicity in a murine model. Blood 117, 3311-3319 (2011).
64. Christine, C. W. et al. Safety and tolerability of putaminal AADC gene therapy for Parkinson disease. Neurology 73, 1662-1669 (2009).
65. Eberling, J. L. et al. Results from a phase I safety trial of hAADC gene therapy for Parkinson disease. Neurology 70, 1980-1983 (2008).
66. Kaplitt, M. G. et al. 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, 2097-2105 (2007). (Pubitemid 46935946)
67. Marks, W. J. Jr. et al. Gene delivery of AAV2-neurturin for Parkinson's disease: a double-blind, randomised, controlled trial. Lancet Neurol. 9, 1164-1172 (2010).
68. Marks, W. J. Jr. et al. Safety and tolerability of intraputaminal delivery of CERE-120 (adeno-associated virus serotype 2-neurturin) to patients with idiopathic Parkinson's disease: an open-label, phase I trial. Lancet Neurol. 7, 400-408 (2008).
69. LeWitt, P. A. et al. AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial. Lancet Neurol. 10, 309-319 (2011).
70. Davidson, B. L. & McCray, P. B. Jr. Current prospects for RNA interference-based therapies. Nature Rev Genet. 12, 329-340 (2011).
71. Davidson, B. L. et al. Recombinant adeno-associated virus type 2, 4, and 5 vectors: transduction of variant cell types and regions in the mammalian central nervous system. Proc. Natl Acad. Sci. USA 97, 3428-3432 (2000). (Pubitemid 30183319)
72. Cabrera-Salazar, M. A. et al. Timing of therapeutic intervention determines functional and survival outcomes in a mouse model of late infantile Batten disease. Mol. Ther. 15, 1782-1788 (2007). (Pubitemid 47434184)
73. Cearley, C. N. & Wolfe, J. H. Transduction characteristics of adeno-associated virus vectors expressing cap serotypes 7, 8, 9, and Rh10 in the mouse brain. Mol. Ther. 13, 528-537 (2006). (Pubitemid 43257620)
74. Chen, Y. H., Chang, M. & Davidson, B. L Molecular signatures of disease brain endothelia provide new sites for CNS-directed enzyme therapy. Nature Med. 15, 1215-1218 (2009).
75. Gray, S. J. et al. Directed evolution of a novel adeno-associated virus (AAV) vector that crosses the seizure-compromised blood-brain barrier (BBB). Mol. Ther. 18, 570-578 (2010).
76. Foust, K. D. et al. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nature Biotech. 27, 59-65 (2009).
77. Fu, H., Dirosario, J., Killedar, S., Zaraspe, K. & McCarty, D. M. Correction of neurological disease of mucopolysaccharidosis IIIB in adult mice by rAAV9 trans-blood-brain barrier gene delivery. Mol. Ther. 8 Mar 2011 (doi:10.1038/mt.2011.34).
78. Duque, S. et al. Intravenous administration of self-complementary AAV9 enables transgene delivery to adult motor neurons. Mol. Ther. 17, 1187-1196 (2009).
79. Inagaki, K. et al. Robust systemic transduction with AAV9 vectors in mice: efficient global cardiac gene transfer superior to that of AAV8. Mol. Ther. 14, 45-53 (2006). (Pubitemid 43899488)
80. Bobo, R. H. et al. Convection-enhanced delivery of macromolecules in the brain. Proc. Natl Acad. Sci. USA 91, 2076-2080 (1994).
81. Kells, A. P. et al. Efficient gene therapy-based method for the delivery of therapeutics to primate cortex. Proc. Natl Acad. Sci. USA 106, 2407-2411 (2009).
82. Liu, G., Martins, I., Wemmie, J. A., Chiorini, J. A. & Davidson, B. L. Functional correction of CNS phenotypes in a lysosomal storage disease model using adeno-associated virus type 4 vectors. J. Neurosci. 25, 9321-9327 (2005). (Pubitemid 41464744)
83. Harper, S. Q. et al. RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model. Proc. Natl Acad. Sci. USA 102, 5820-5825 (2005). (Pubitemid 40559643)
84. Palfi, S. et al. ProSavin® a gene therapy approach for Parkinson disease: Phase I clinical trial update. Hum. Gene Ther. 21, 1364 (2010)
85. Mandel, R. J. CERE-1 10, an adeno-associated virus-based gene delivery vector expressing human nerve growth factor for the treatment of Alzheimer's disease. Curr. Opin. Mol. Ther. 12, 240-247 (2010).
86. Binder, D. K., Rau, G. M. & Starr, P. A. Risk factors for hemorrhage during microelectrode-guided deep brain stimulator implantation for movement disorders. Neurosurgery 56, 722-732 (2005).
87. Matalon, R. et al. Aspartoacylase deficiency and N-acetylaspartic aciduria in patients with Canavan disease. Am. J. Med. Genet. 29, 463-471 (1988). (Pubitemid 18068275)
88. Janson, C. et al. Clinical protocol. Gene therapy of Canavan disease: AAV-2 vector for neurosurgical delivery of aspartoacylase gene (ASPA) to the human brain. Hum. Gene Ther. 13, 1391-1412 (2002). (Pubitemid 35034518)
89. McPhee, S. W et al. Immune responses to AAV in a phase I study for Canavan disease. J. Gene Med. 8, 577-588 (2006). (Pubitemid 43827251)
90. Worgall, S. et al. Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA. Hum. Gene Ther. 19, 463-474 (2008). (Pubitemid 351748791)
91. Hofman, S. & Peltonen, L. The Neuronal Ceroid Lipofuscinoses (eds Scriver, C, Beaudet, A., Sly, W & Valle, D.) (McGraw-Hill, New York, 2001).
92. Sondhi, D. et al. Enhanced survival of the LINCL mouse following CLN2 gene transfer using the rh.10 rhesus macaque-derived adeno-associated virus vector. Mol. Ther. 15, 481-491 (2007).
93. Brooks, A. I. et al. Functional correction of established central nervous system deficits in an animal model of lysosomal storage disease with feline immunodeficiency virus-based vectors. Proc. Natl Acad. Sci. USA 99, 6216-6221 (2002). (Pubitemid 34493292)
94. Mattsson, N. et al. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA 302, 385-393 (2009).
95. Mendell, J. R. et al. Sustained α-sarcoglycan gene expression after gene transfer in limb-girdle muscular dystrophy, type 2D. Ann. Neurol. 68, 629-638 (2010).
96. Mendell, J. R. et al. Limb-girdle muscular dystrophy type 2D gene therapy restores α-sarcoglycan and associated proteins. Ann. Neurol. 66, 290-297 (2009).
97. Mendell, J. R. et al. Dystrophin immunity in Duchenne's muscular dystrophy. N. Engl. J. Med. 363, 1429-1437 (2010).
98. Mas, A. et al. Reversal of type 1 diabetes by engineering a glucose sensor in skeletal muscle. Diabetes 55, 1546-1553 (2006). (Pubitemid 44324106)
99. Kay, M. A. et al. Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector. Nature Genet. 24, 257-261 (2000). (Pubitemid 30132193)
100. Hanley, J. P. et al. Investigation of chronic hepatitis C infection in individuals with haemophilia: assessment of invasive and non-invasive methods. Br. J. Haematol. 94, 159-165 (1996). (Pubitemid 26232559)
101. Brantly, M. L. et al. Phase I trial of intramuscular injection of a recombinant adeno-associated virus serotype 2 αl-antitrypsin (AAT) vector in AAT-deficient adults. Hum. Gene Ther. 17, 1177-1186 (2006). (Pubitemid 44975135)
102. Brantly, M. L. et al. Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy. Proc. Natl Acad. Sci. USA 106, 16363-16368 (2009).
103. Stroes, E. S. et al. Intramuscular administration of AAV1-lipoprotein lipase S447X lowers triglycerides in lipoprotein lipase-deficient patients. Arterioscler. Thromb. Vasc. Biol. 28, 2303-2304 (2008).
104. Arruda, V. R. et al. Lack of germline transmission of vector sequences following systemic administration of recombinant AAV-2 vector in males. Mol. Ther. 4, 586-592 (2001). (Pubitemid 34026874)
105. Herzog, R. W. et al. Influence of vector dose on factor IX-specific T and B cell responses in muscle-directed gene therapy. Hum. Gene Ther. 13, 1281-1291 (2002). (Pubitemid 35034508)
106. Herzog, R. W. et al. Long-term correction of canine hemophilia B by gene transfer of blood coagulation factor IX mediated by adeno-associated viral vector. Nature Med. 5, 56-63 (1999). (Pubitemid 29050999)
107. Chao, H. et al. Several log increase in therapeutic transgene delivery by distinct adeno-associated viral serotype vectors. Mol. Ther. 2, 619-623 (2000).
108. Arruda, V. R. et al. Safety and efficacy of factor IX gene transfer to skeletal muscle in murine and canine hemophilia B models by adeno-associated viral vector serotype 1. Blood 103, 85-92 (2004). (Pubitemid 38029922)
109. Lu, Y. et al. Therapeutic level of functional human α 1 antitrypsin (hAAT) secreted from murine muscle transduced by adeno-associated virus (rAAV1) vector. J. Gene Med. 8, 730-735 (2006).
110. Su, L. T. et al. Uniform scale-independent gene transfer to striated muscle after transvenular extravasation of vector. Circulation 112, 1780-1788 (2005). (Pubitemid 41368154)
111. Arruda, V. R. et al. Peripheral transvenular delivery of adeno-associated viral vectors to skeletal muscle as a novel therapy for hemophilia B. Blood 115, 4678-4688 (2010).
112. Haurigot, V. et al. Safety of AAV factor IX peripheral transvenular gene delivery to muscle in hemophilia B dogs. Mol. Ther. 18, 1318-1329 (2010).
113. Rodino-Klapac, L. R. et al. Persistent expression of FLAG-tagged micro dystrophin in nonhuman primates following intramuscular and vascular delivery. Mol. Ther. 18, 109-117 (2010).
114. Powers, W. et al. Safety and feasibility of transvenous limb perfusion with saline in human muscular dystrophy. Mol. Ther. 18 (Suppl. 1), 126 (2010).
115. Toromanoff, A. et al. Lack of immunotoxicity after regional intravenous (RI) delivery of rAAV to nonhuman primate skeletal muscle. Mol. Ther. 18, 151-160 (2010).
116. Mingozzi, F. et al. AAV-1-mediated gene transfer to skeletal muscle in humans results in dose-dependent activation of capsid-specific T cells. Blood 114, 2077-2086 (2009).
117. Mingozzi, F. et al. Modulation of T cell response to the AAV capsid in subjects undergoing intramuscular gene transfer for lipoprotein lipase deficiency. Hum. Gene Ther. 19, 1090 (2008).
118. Hudig, D., Haverty, T., Fulcher, C, Redelman, D. & Mendelsohn, J. Inhibition of human natural cytotoxicity by macromolecular antiproteases. J. Immunol. 126, 1569-1574 (1981). (Pubitemid 11149266)
119. Matzinger, P. The danger model: a renewed sense of self. Science 296, 301-305 (2002) (Pubitemid 34303674)
120. Velazquez, V. M., Bowen, D. G. & Walker, C. M. Silencing of T lymphocytes by antigen-driven programmed death in recombinant adeno-associated virus vector-mediated gene therapy. Blood 113, 538-545 (2009).
121. Wright, J. F. Manufacturing and characterizing AAV-based vectors for use in clinical studies. Gene Ther. 15, 840-848 (2008). (Pubitemid 351712617)
122. Lock, M. et al. Characterization of a recombinant adeno-associated virus type 2 reference standard material. Hum. Gene Ther. 21, 1273-1285 (2010).
123. Urnov, F. D., Rebar, E. J., Holmes, M. C, Zhang, H. S. & Gregory, P. D. Genome editing with engineered zinc finger nucleases. Nature Rev. Genet. 11, 636-646 (2010).
124. Kang, E. M. et al. Retrovirus gene therapy for X-linked chronic granulomatous disease can achieve stable long-term correction of oxidase activity in peripheral blood neutrophils. Blood 115, 783-791 (2010).
125. European Society of Gene Therapy. One of three successfully treated CGD patients in a Swiss-German gene therapy trial died due to his underlying disease: a position statement from the European Society of Gene Therapy (ESGT). J. Gene Med. 8, 1435 (2006).
126. Hacein-Bey-Abina, S. et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J. Clin. Invest 118, 3132-3142 (2008).
127. Hacein-Bey-Abina, S. et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302, 415-419 (2003). (Pubitemid 37296260)
128. Grimm, D. et al. Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature 441, 537-541 (2006). (Pubitemid 44050158)
129. Ross, C. J. et al. 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, 487-499 (2006). (Pubitemid 43794488)
130. Walter, J., You, Q., Hagstrom, J. N., Sands, M. & High, K. A. Successful expression of human factor IX following repeat administration of adenoviral vector in mice. Proc. Natl Acad. Sci. USA 93, 3056-3061 (1996). (Pubitemid 26114362)
131. Favre, D. et al. Immediate and long-term safety of recombinant adeno-associated virus injection into the nonhuman primate muscle. Mol. Ther. 4, 559-566 (2001). (Pubitemid 34026871)
132. Gene therapy and the germline. Nature Med. 5, 245 (1999).
133. Favaro, P. et al. Host and vector-dependent effects on the risk of germline transmission of AAV vectors. Mol. Ther. 17, 1022-1030 (2009).
134. Schuettrumpf, J. et al. Inadvertent germline transmission of AAV2 vector: findings in a rabbit model correlate with those in a human clinical trial. Mol. Ther. 13, 1064-1073 (2006). (Pubitemid 43779181)
135. Srivastava, A., Lusby, E. W. & Berns, K. I. Nucleotide sequence and organization of the adeno-associated virus 2 genome. J. Virol. 45, 555-564 (1983). (Pubitemid 13225420)
136. Dong, J. Y., Fan, P. D. & Frizzell, R. A. Quantitative analysis of the packaging capacity of recombinant adeno-associated virus. Hum. Gene Ther. 7, 2101-2112 (1996). (Pubitemid 26400735)
137. Matsushita, T. et al. Adeno-associated virus vectors can be efficiently produced without helper virus. Gene Ther. 5, 938-945 (1998). (Pubitemid 28371911)
138. Gao, G. P. et al. Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. Proc. Natl Acad. Sci. USA 99, 11854-11859 (2002).
139. Nakai, H. et al. AAV serotype 2 vectors preferentially integrate into active genes in mice. Nature Genet. 34, 297-302 (2003). (Pubitemid 36792862)
140. Miller, D. G., Rutledge, E. A. & Russell, D. W Chromosomal effects of adeno-associated virus vector integration. Nature Genet. 30, 147-148 (2002).
141. Wright, J. F., Wellman, J. & High, K. A. Manufacturing and regulatory strategies for clinical AAV2-hRPE65. Curr. Gene Ther. 10, 341-349 (2010).
142. Powell, J. S. et al. Phase 1 trial of FVIII gene transfer for severe hemophilia A using a retroviral construct administered by peripheral intravenous infusion. Blood 102, 2038-2045 (2003). (Pubitemid 37122377)
143. Xu, L. et al. Absence of a desmopressin response after therapeutic expression of factor VIII in hemophilia A dogs with liver-directed neonatal gene therapy. Proc. Natl Acad. Sci. USA 102, 6080-6085 (2005). (Pubitemid 40594258)
144. Cavazzana-Calvo, M. et al. Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia. Nature 467, 318-322 (2010).
145. Driskell, R. R. & Engelhardt, J. F. Current status of gene therapy for inherited lung diseases. Ann. Rev Physiol. 65, 585-512 (2003).
146. Chuah, M. K., Collen, D. & VandenDriessche, T. Clinical gene transfer studies for hemophilia A. Semin. Thromb. Hemost 30, 249-256 (2004). (Pubitemid 38582328)
147. Brunetti-Pierri, N. et al. Efficient, long-term hepatic gene transfer using clinically relevant HDAd doses by balloon occlusion catheter delivery in nonhuman primates. Mol. Ther. 17, 327-333 (2009).
148. Jiang, H. et al. 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 (2006). (Pubitemid 44184967)
149. Le, M. et al. Therapeutic levels of functional human factor X in rats after retroviral-mediated hepatic gene therapy. Blood 89, 1254-1259 (1997). (Pubitemid 27079989)
150. Muzyczka, N. & Berns, K. I. in Parvoviridae: The Viruses and their Replication (eds Knipe, D. M. & Howley, P. M.) 2437-2477 (Lippincott, Williams and Wilkins, Philadelphia, 2001).
151. Yan, Z. et al. Ubiquitination of both adeno-associated virus type 2 and 5 capsid proteins affects the transduction efficiency of recombinant vectors. J. Virol. 76, 2043-2053 (2002). (Pubitemid 34150672)
152. Finn, J. D. et al. Proteasome inhibitors decrease AAV2 capsid derived peptide epitope presentation on MHC class I following transduction. Mol. Ther. 18, 135-142 (2010).
153. Thomas, C. E., Storm, T. A., Huang, Z. & Kay, M. A. Rapid uncoating of vector genomes is the key to efficient liver transduction with pseudotyped adeno-associated virus vectors. J. Virol. 78, 3110-3122 (2004). (Pubitemid 38314369)
154. Aitken, M. L. et al. A phase I study of aerosolized administration of
155. Moss, R. B. et al. Repeated aerosolized AAV-CFTR for treatment of cystic fibrosis: a randomized placebo-controlled phase 2B trial. Hum. Gene Ther 18, 726-732 (2007). (Pubitemid 47378069)
156. Wagner, J. A. et al. Safety and biological efficacy of an adeno-associated virus vector-cystic fibrosis transmembrane regulator (AAV-CFTR) in the cystic fibrosis maxillary sinus. Laryngoscope 109, 266-274 (1999). (Pubitemid 29075570)
157. Wagner, J. A. et al. A phase II, double-blind, randomized, placebo-controlled clinical trial of tgAAVCF using maxillary sinus delivery in patients with cystic fibrosis with antrostomies. Hum. Gene Ther. 13, 1349-1359 (2002). (Pubitemid 35034514)
158. Wagner, J. A. et al. Efficient and persistent gene transfer of AAV-CFTR in maxillary sinus. Lancet 351, 1702-1703 (1998). (Pubitemid 28254535)
159. Jaski, B. E. et al. Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID Trial), a first-in-human phase 1/2 clinical trial. J. Card. Fail. 15, 171-181 (2009).
160. Frank, K. M. et al. Investigation of the cause of death in a gene-therapy trial. N. Engl. J. Med. 361, 161-169 (2009).
161. Mease, P. J. et al. Local delivery of a recombinant adenoassociated vector containing a tumour necrosis factor α antagonist gene in inflammatory arthritis: a phase 1 dose-escalation safety and tolerability study. Ann. Rheum. Dis. 68, 1247-1254 (2009).
162. Mease, P. J. et al. Safety, tolerability, and clinical outcomes after intraarticular injection of a recombinant adeno-associated vector containing a tumor necrosis factor antagonist gene: results of a phase 1/2 study. J. Rheumatol. 37, 692-703 (2010).
163. Cardone, M. et al. Correction of Hunter syndrome in the MPSII mouse model by AAV2/8-mediated gene delivery. Hum. Mol. Genet. 15, 1225-1236 (2006).
164. McEachern, K. A. et al. AAV8-mediated expression of glucocerebrosidase ameliorates the storage pathology in the visceral organs of a mouse model of Gaucher disease. J. Gene Med. 8, 719-729 (2006).
165. Seppen, J. et al. Adeno-associated virus vector serotypes mediate sustained correction of bilirubin UDP glucuronosyltransferase deficiency in rats. Mol. Ther. 13, 1085-1092 (2006). (Pubitemid 43779183)
166. Koeberl, D. D. et al. Early, sustained efficacy of adeno-associated virus vector-mediated gene therapy in glycogen storage disease type Ia. Gene Ther. 13, 1281-1289 (2006). (Pubitemid 44264082)
167. Park, E. S., Oh, H. J., Kruger, W. D., Jung, S. C. & Lee, J. S. Recombinant adeno-associated virus mediated gene transfer in a mouse model for homocystinuria. Exp. Mol. Med. 38, 652-661 (2006). (Pubitemid 46103587)
168. Scallan, C. D. et al. Sustained phenotypic correction of canine hemophilia A using an adeno-associated viral vector. Blood 102, 2031-2037 (2003). (Pubitemid 37122376)
169. Daly, T. M., Ohlemiller, K. K., Roberts, M. S., Vogler, C. A. & Sands, M. S. Prevention of systemic clinical disease in MPS VII mice following AAV-mediated neonatal gene transfer. Gene Ther. 8, 1291-1298 (2001). (Pubitemid 32834297)
170. Watson, G. et al. Intrathecal administration of AAV vectors for the treatment of lysosomal storage in the brains of MPS I mice. Gene Ther. 13, 917-925 (2006).
171. Gao, J. et al. Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice. Blood 115, 3374-3381 (2011).
172. Conlon, T. J. et al. Efficient hepatic delivery and expression from a recombinant adeno-associated virus 8 pseudotyped α 1-antitrypsin vector. Mol. Ther. 12, 867-875 (2005). (Pubitemid 41614482)
173. Ding, Z. et al. Correction of murine PKU following AAV-mediated intramuscular expression of a complete phenylalanine hydroxylating system. Mol. Ther. 16, 673-681 (2008). (Pubitemid 351426168)
174. Jung, S. C. et al. Adeno-associated viral vector-mediated gene transfer results in long-term enzymatic and functional correction in multiple organs of Fabry mice. Proc. Natl Acad. Sci. USA 98, 2676-2681 (2001).
175. Lebherz, C. et al. Gene therapy with novel adeno-associated virus vectors substantially diminishes atherosclerosis in a murine model of familial hypercholesterolemia. J. Gene Med. 6, 663-672 (2004). (Pubitemid 40228082)
176. Chandler, R. J. et al. Adeno-associated virus serotype 8 (AAV8) Gene transfer rescues a neonatal lethal murine model of propionic acidemia. Hum. Gene Ther. 16 Feb 2011 (doi:10.1089/hum.2010.164).