Rare Diseases pp 131-157 | Cite as

Adeno-Associated Virus Gene Therapy and Its Application to the Prevention and Personalised Treatment of Rare Diseases

  • Konstantina GrosiosEmail author
  • Harald Petry
  • Jacek Lubelski
Part of the Advances in Predictive, Preventive and Personalised Medicine book series (APPPM, volume 6)


Gene therapy has always found a home in rare diseases and the approval of Glybera® for lipoprotein lipase deficiency has marked a major milestone in gene therapy and has brought this type of therapy even closer to clinical practice. There is little closer to the personalisation of medicine than the ability to repair or restore the function of a person’s own faulty genes, the core principle of gene therapy. It is therefore reasonable to argue that gene therapy is the ultimate personalised medicine. At the same time, advances in scientific understanding and technological ability to analyse the human genome imply that gene therapy could also be used to prevent the development of disease. Using examples from the AAV-based gene therapy field as is applied to rare diseases, the first section of this chapter aims to illustrate how gene therapy aligns to the principles of PPPM whereas the second part of the chapter intends to provide an in depth review of the developments in the AAV field that underpin the use of these viruses as gene therapy delivery systems.

PPPM-Related Keywords

Gene therapy Adeno-associated viral vectors Rare disease prevention Rare disease personalised treatment Alipogene tiparvovec Glybera® Predictive, preventive and personalised medicine 


  1. 1.
    Buning H (2013) Gene therapy enters the pharma market: the short story of a long journey. EMBO Mol Med 5(1):1–3. doi: 10.1002/emmm.201202291 PubMedPubMedCentralGoogle Scholar
  2. 2.
    Blaese RM, Culver KW, Miller AD, Carter CS, Fleisher T, Clerici M, Shearer G, Chang L, Chiang Y, Tolstoshev P, Greenblatt JJ, Rosenberg SA, Klein H, Berger M, Mullen CA, Ramsey WJ, Muul L, Morgan RA, Anderson WF (1995) T lymphocyte-directed gene therapy for ADA- SCID: initial trial results after 4 years. Science 270(5235):475–480PubMedGoogle Scholar
  3. 3.
    Rivat C, Santilli G, Gaspar HB, Thrasher AJ (2012) Gene therapy for primary immunodeficiencies. Hum Gene Ther 23(7):668–675. doi: 10.1089/hum.2012.116 PubMedPubMedCentralGoogle Scholar
  4. 4.
    Cavazzana-Calvo M, Hacein-Bey S, de Saint BG, Gross F, Yvon E, Nusbaum P, Selz F, Hue C, Certain S, Casanova JL, Bousso P, Deist FL, Fischer A (2000) Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 288(5466):669–672PubMedGoogle Scholar
  5. 5.
    Hacein-Bey-Abina S, Fischer A, Cavazzana-Calvo M (2002) Gene therapy of X-linked severe combined immunodeficiency. Int J Hematol 76(4):295–298PubMedGoogle Scholar
  6. 6.
    Cavazzana-Calvo M, Fischer A, Hacein-Bey-Abina S, Aiuti A (2012) Gene therapy for primary immunodeficiencies: part 1. Curr Opin Immunol 24(5):580–584. doi: 10.1016/j.coi.2012.08.008 PubMedGoogle Scholar
  7. 7.
    Ginn SL, Alexander IE, Edelstein ML, Abedi MR, Wixon J (2013) Gene therapy clinical trials worldwide to 2012 – an update. J Gene Med 15(2):65–77. doi: 10.1002/jgm.2698 PubMedGoogle Scholar
  8. 8.
    Golubnitschaja O (2010) Time for new guidelines in advanced diabetes care: paradigm change from delayed interventional approach to predictive, preventive & personalized medicine. EPMA J 1(1):3–12. doi: 10.1007/s13167-010-0014-5 PubMedPubMedCentralGoogle Scholar
  9. 9.
    Golubnitschaja O, Costigliola V, EPMA (2012) General report & recommendations in predictive, preventive and personalised medicine 2012: white paper of the European Association for Predictive, Preventive and Personalised Medicine. EPMA J 3(1):14. doi: 10.1186/1878-5085-3-14 PubMedPubMedCentralGoogle Scholar
  10. 10.
    Thomas CE, Ehrhardt A, Kay MA (2003) Progress and problems with the use of viral vectors for gene therapy. Nat Rev Genet 4(5):346–358. doi: 10.1038/nrg1066 PubMedGoogle Scholar
  11. 11.
    Asokan A, Schaffer DV, Samulski RJ (2012) The AAV vector toolkit: poised at the clinical crossroads. Mol Ther Journal Am Soc Gene Ther 20(4):699–708. doi: 10.1038/mt.2011.287 Google Scholar
  12. 12.
    Buning H, Perabo L, Coutelle O, Quadt-Humme S, Hallek M (2008) Recent developments in adeno-associated virus vector technology. J Gene Med 10(7):717–733. doi: 10.1002/jgm.1205 PubMedGoogle Scholar
  13. 13.
    Ortolano S, Spuch C, Navarro C (2012) Present and future of adeno associated virus based gene therapy approaches. Recent Pat Endocr Metab Immune Drug Discov 6(1):47–66PubMedGoogle Scholar
  14. 14.
    Mingozzi F, High KA (2011) Therapeutic in vivo gene transfer for genetic disease using AAV: progress and challenges. Nat Rev Genet 12(5):341–355. doi: 10.1038/nrg2988 PubMedGoogle Scholar
  15. 15.
    Gaudet D, Methot J, Dery S, Brisson D, Essiembre C, Tremblay G, Tremblay K, de Wal J, Twisk J, van den Bulk N, Sier-Ferreira V, van Deventer S (2013) Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene therapy for lipoprotein lipase deficiency: an open-label trial. Gene Ther 20(4):361–369. doi: 10.1038/gt.2012.43 PubMedGoogle Scholar
  16. 16.
    Wion KL, Kirchgessner TG, Lusis AJ, Schotz MC, Lawn RM (1987) Human lipoprotein lipase complementary DNA sequence. Science 235(4796):1638–1641PubMedGoogle Scholar
  17. 17.
    Langlois S, Deeb S, Brunzell JD, Kastelein JJ, Hayden MR (1989) A major insertion accounts for a significant proportion of mutations underlying human lipoprotein lipase deficiency. Proc Natl Acad Sci U S A 86(3):948–952PubMedPubMedCentralGoogle Scholar
  18. 18.
    Rahalkar AR, Giffen F, Har B, Ho J, Morrison KM, Hill J, Wang J, Hegele RA, Joy T (2009) Novel LPL mutations associated with lipoprotein lipase deficiency: two case reports and a literature review. Can J Physiol Pharmacol 87(3):151–160. doi: 10.1139/y09-005 PubMedGoogle Scholar
  19. 19.
    Santamarina-Fojo S (1998) The familial chylomicronemia syndrome. Endocrinol Metab Clin North Am 27(3):551–567, viiiPubMedGoogle Scholar
  20. 20.
    Frank R, Hargreaves R (2003) Clinical biomarkers in drug discovery and development. Nat Rev Drug Discov 2(7):566–580. doi: 10.1038/nrd1130 PubMedGoogle Scholar
  21. 21.
    Agbandje-McKenna M, Kleinschmidt J (2011) AAV capsid structure and cell interactions. Methods Mol Biol 807:47–92. doi: 10.1007/978-1-61779-370-7_3, Clifton, NJPubMedGoogle Scholar
  22. 22.
    Howard DB, Powers K, Wang Y, Harvey BK (2008) Tropism and toxicity of adeno-associated viral vector serotypes 1, 2, 5, 6, 7, 8, and 9 in rat neurons and glia in vitro. Virology 372(1):24–34. doi: 10.1016/j.virol.2007.10.007 PubMedPubMedCentralGoogle Scholar
  23. 23.
    Taymans JM, Vandenberghe LH, Haute CV, Thiry I, Deroose CM, Mortelmans L, Wilson JM, Debyser Z, Baekelandt V (2007) Comparative analysis of adeno-associated viral vector serotypes 1, 2, 5, 7, and 8 in mouse brain. Hum Gene Ther 18(3):195–206. doi: 10.1089/hum.2006.178 PubMedGoogle Scholar
  24. 24.
    Stroes ES, Nierman MC, Meulenberg JJ, Franssen R, Twisk J, Henny CP, Maas MM, Zwinderman AH, Ross C, Aronica E, High KA, Levi MM, Hayden MR, Kastelein JJ, Kuivenhoven JA (2008) Intramuscular administration of AAV1-lipoprotein lipase S447X lowers triglycerides in lipoprotein lipase-deficient patients. Arterioscler Thromb Vasc Biol 28(12):2303–2304. doi: 10.1161/ATVBAHA.108.175620 PubMedGoogle Scholar
  25. 25.
    Salegio EA, Samaranch L, Kells AP, Forsayeth J, Bankiewicz K (2012) Guided delivery of adeno-associated viral vectors into the primate brain. Adv Drug Deliv Rev 64(7):598–604. doi: 10.1016/j.addr.2011.10.005 PubMedPubMedCentralGoogle Scholar
  26. 26.
    Pike LS, Tannous BA, Deliolanis NC, Hsich G, Morse D, Tung CH, Sena-Esteves M, Breakefield XO (2011) Imaging gene delivery in a mouse model of congenital neuronal ceroid lipofuscinosis. Gene Ther 18(12):1173–1178. doi: 10.1038/gt.2011.118 PubMedPubMedCentralGoogle Scholar
  27. 27.
    Yin L, Greenberg K, Hunter JJ, Dalkara D, Kolstad KD, Masella BD, Wolfe R, Visel M, Stone D, Libby RT, Diloreto D Jr, Schaffer D, Flannery J, Williams DR, Merigan WH (2011) Intravitreal injection of AAV2 transduces macaque inner retina. Invest Ophthalmol Vis Sci 52(5):2775–2783. doi: 10.1167/iovs.10-6250 PubMedPubMedCentralGoogle Scholar
  28. 28.
    Wang Z, Storb R, Lee D, Kushmerick MJ, Chu B, Berger C, Arnett A, Allen J, Chamberlain JS, Riddell SR, Tapscott SJ (2010) Immune responses to AAV in canine muscle monitored by cellular assays and noninvasive imaging. Mol Ther 18(3):617–624. doi: 10.1038/mt.2009.294 PubMedPubMedCentralGoogle Scholar
  29. 29.
    Tarantal AF, Lee CC (2010) Long-term luciferase expression monitored by bioluminescence imaging after adeno-associated virus-mediated fetal gene delivery in rhesus monkeys (Macaca mulatta). Hum Gene Ther 21(2):143–148. doi: 10.1089/hum.2009.126 PubMedPubMedCentralGoogle Scholar
  30. 30.
    Kelloff GJ, Sigman CC (2012) Cancer biomarkers: selecting the right drug for the right patient. Nat Rev Drug Discov 11(3):201–214. doi: 10.1038/nrd3651 PubMedGoogle Scholar
  31. 31.
    Zwierzina H (2008) Biomarkers in drug development. Ann Oncol Off J Eur Soc Med Oncol/ESMO 19(Suppl 5):v33–v37. doi: 10.1093/annonc/mdn309 Google Scholar
  32. 32.
    Nathwani AC, Tuddenham EG, Rangarajan S, Rosales C, McIntosh J, Linch DC, Chowdary P, Riddell A, Pie AJ, Harrington C, O’Beirne J, Smith K, Pasi J, Glader B, Rustagi P, Ng CY, Kay MA, Zhou J, Spence Y, Morton CL, Allay J, Coleman J, Sleep S, Cunningham JM, Srivastava D, Basner-Tschakarjan E, Mingozzi F, High KA, Gray JT, Reiss UM, Nienhuis AW, Davidoff AM (2011) Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med 365(25):2357–2365. doi: 10.1056/NEJMoa1108046 PubMedPubMedCentralGoogle Scholar
  33. 33.
    O’Mahony B, Noone D, Giangrande PL, Prihodova L (2013) Haemophilia care in Europe – a survey of 35 countries. Haemophilia 19(4):e239–e247. doi: 10.1111/hae.12125 PubMedGoogle Scholar
  34. 34.
    Carpentier AC, Frisch F, Labbe SM, Gagnon R, de Wal J, Greentree S, Petry H, Twisk J, Brisson D, Gaudet D (2012) Effect of alipogene tiparvovec (AAV1-LPL(S447X)) on postprandial chylomicron metabolism in lipoprotein lipase-deficient patients. J Clin Endocrinol Metab 97(5):1635–1644. doi: 10.1210/jc.2011-3002 PubMedGoogle Scholar
  35. 35.
    Bryant LM, Christopher DM, Giles AR, Hinderer C, Rodriguez JL, Smith JB, Traxler EA, Tycko J, Wojno AP, Wilson JM (2013) Lessons learned from the clinical development and market authorization of glybera. Hum Gene Therapy Clin Dev 24(2):55–64. doi: 10.1089/humc.2013.087 Google Scholar
  36. 36.
    Trusheim MR, Berndt ER, Douglas FL (2007) Stratified medicine: strategic and economic implications of combining drugs and clinical biomarkers. Nat Rev Drug Discov 6(4):287–293. doi: 10.1038/nrd2251 PubMedGoogle Scholar
  37. 37.
    Griggs RC, Batshaw M, Dunkle M, Gopal-Srivastava R, Kaye E, Krischer J, Nguyen T, Paulus K, Merkel PA, Rare Diseases Clinical Research N (2009) Clinical research for rare disease: opportunities, challenges, and solutions. Mol Genet Metab 96(1):20–26. doi: 10.1016/j.ymgme.2008.10.003 PubMedPubMedCentralGoogle Scholar
  38. 38.
    Heemstra HE, van Weely S, Buller HA, Leufkens HG, de Vrueh RL (2009) Translation of rare disease research into orphan drug development: disease matters. Drug Discov Today 14(23–24):1166–1173. doi: 10.1016/j.drudis.2009.09.008 PubMedGoogle Scholar
  39. 39.
    Harskamp RE, Lopes RD, Baisden CE, de Winter RJ, Alexander JH (2013) Saphenous vein graft failure after coronary artery bypass surgery: pathophysiology, management, and future directions. Ann Surg 257(5):824–833. doi: 10.1097/SLA.0b013e318288c38d PubMedGoogle Scholar
  40. 40.
    Zhang X, Zhuang J, Wu H, Chen Z, Su J, Chen S, Chen J (2010) Inhibitory effects of calcitonin gene-related peptides on experimental vein graft disease. Ann Thorac Surg 90(1):117–123. doi: 10.1016/j.athoracsur.2010.03.063 PubMedGoogle Scholar
  41. 41.
    Maeda Y, Shimada K, Ikeda U (2004) Gene transfer of nitric oxide synthase via the use of adeno-associated virus vectors. Methods Mol Biol 279:213–224. doi: 10.1385/1-59259-807-2:213, Clifton, NJPubMedGoogle Scholar
  42. 42.
    Work LM, Buning H, Hunt E, Nicklin SA, Denby L, Britton N, Leike K, Odenthal M, Drebber U, Hallek M, Baker AH (2006) Vascular bed-targeted in vivo gene delivery using tropism-modified adeno-associated viruses. Mol Ther J Am Soc Gene Ther 13(4):683–693. doi: 10.1016/j.ymthe.2005.11.013 Google Scholar
  43. 43.
    Sabatino DE, Mackenzie TC, Peranteau W, Edmonson S, Campagnoli C, Liu YL, Flake AW, High KA (2007) Persistent expression of hF.IX After tolerance induction by in utero or neonatal administration of AAV-1-F.IX in hemophilia B mice. Mol Ther 15(9):1677–1685. doi: 10.1038/ PubMedGoogle Scholar
  44. 44.
    Mattar CN, Nathwani AC, Waddington SN, Dighe N, Kaeppel C, Nowrouzi A, McIntosh J, Johana NB, Ogden B, Fisk NM, Davidoff AM, David A, Peebles D, Valentine MB, Appelt JU, von Kalle C, Schmidt M, Biswas A, Choolani M, Chan JK (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(11):1950–1960. doi: 10.1038/mt.2011.107 PubMedPubMedCentralGoogle Scholar
  45. 45.
    Roybal JL, Endo M, Radu A, Gray L, Todorow CA, Zoltick PW, Lutsenko S, Flake AW (2012) Early gestational gene transfer with targeted ATP7B expression in the liver improves phenotype in a murine model of Wilson’s disease. Gene Ther 19(11):1085–1094. doi: 10.1038/gt.2011.186 PubMedGoogle Scholar
  46. 46.
    Sugano H, Matsumoto T, Miyake K, Watanabe A, Iijima O, Migita M, Narisawa S, Millan JL, Fukunaga Y, Shimada T (2012) Successful gene therapy in utero for lethal murine hypophosphatasia. Hum Gene Ther 23(4):399–406. doi: 10.1089/hum.2011.148 PubMedPubMedCentralGoogle Scholar
  47. 47.
    Golubnitschaja O, Watson ID, Topic E, Sandberg S, Ferrari M, Costigliola V (2013) Position paper of the EPMA and EFLM: a global vision of the consolidated promotion of an integrative medical approach to advance health care. EPMA J 4(1):12. doi: 10.1186/1878-5085-4-12 PubMedPubMedCentralGoogle Scholar
  48. 48.
    Schieppati A, Henter JI, Daina E, Aperia A (2008) Why rare diseases are an important medical and social issue. Lancet 371(9629):2039–2041. doi: 10.1016/S0140-6736(08)60872-7 PubMedGoogle Scholar
  49. 49.
    Atchison RW, Casto BC, Hammon WM (1966) Electron microscopy of adenovirus-associated virus (AAV) in cell cultures. Virology 29(2):353–357. doi:
  50. 50.
    Samulski RJ, Berns KI, Tan M, Muzyczka N (1982) Cloning of adeno-associated virus into pBR322: rescue of intact virus from the recombinant plasmid in human cells. Proc Natl Acad Sci U S A 79(6):2077–2081PubMedPubMedCentralGoogle Scholar
  51. 51.
    Senapathy P, Carter BJ (1984) Molecular cloning of adeno-associated virus variant genomes and generation of infectious virus by recombination in mammalian cells. J Biol Chem 259(7):4661–4666PubMedGoogle Scholar
  52. 52.
    Fife KH, Berns KI, Murray K (1977) Structure and nucleotide sequence of the terminal regions of adeno-associated virus DNA. Virology 78(2):475–487. doi:
  53. 53.
    Berns KI, Kort J, FIFE KH, Grogan EW, Spear I (1975) Study of the fine structure of adeno-associated virus DNA with bacterial restriction endonucleases. J Virol 16(3):712–719PubMedPubMedCentralGoogle Scholar
  54. 54.
    Berns KI, Kelly Jr TJ (1974) Visualization of the inverted terminal repetition in adeno-associated virus DNA. J Mol Biol 82(2):267–271. doi:
  55. 55.
    Gerry HW, Kelly Jr TJ, Berns KI (1973) Arrangement of nucleotide sequences in adeno-associated virus DNA. J Mol Biol 79(2):207–225. doi:
  56. 56.
    Lusby E, Fife KH, Berns KI (1980) Nucleotide sequence of the inverted terminal repetition in adeno-associated virus DNA. J Virol 34(2):402–409PubMedPubMedCentralGoogle Scholar
  57. 57.
    Maxam AM, Gilbert W (1977) A new method for sequencing DNA. Proc Natl Acad Sci U S A 74(2):560–564PubMedPubMedCentralGoogle Scholar
  58. 58.
    Ryan JH, Zolotukhin S, Muzyczka N (1996) Sequence requirements for binding of Rep68 to the adeno-associated virus terminal repeats. J Virol 70(3):1542–1553PubMedPubMedCentralGoogle Scholar
  59. 59.
    McCarty DM, Ryan JH, Zolotukhin S, Zhou X, Muzyczka N (1994) Interaction of the adeno-associated virus Rep protein with a sequence within the A palindrome of the viral terminal repeat. J Virol 68(8):4998–5006PubMedPubMedCentralGoogle Scholar
  60. 60.
    Chiorini JA, Afione S, Kotin RM (1999) Adeno-associated virus (AAV) type 5 Rep protein cleaves a unique terminal resolution site compared with other AAV serotypes. J Virol 73(5):4293–4298PubMedPubMedCentralGoogle Scholar
  61. 61.
    Wu J, Davis MD, Owens RA (2001) A Rep recognition sequence is necessary but not sufficient for nicking of DNA by adeno-associated virus type-2 Rep proteins. Arch Biochem Biophys 389(2):271–277. doi: 10.1006/abbi.2001.2348 PubMedGoogle Scholar
  62. 62.
    Davis MD, Wu J, Owens RA (2000) Mutational analysis of adeno-associated virus type 2 Rep68 protein endonuclease activity on partially single-stranded substrates. J Virol 74(6):2936–2942PubMedPubMedCentralGoogle Scholar
  63. 63.
    Wu J, Davis MD, Owens RA (1999) Factors affecting the terminal resolution site endonuclease, helicase, and ATPase activities of adeno-associated virus type 2 Rep proteins. J Virol 73(10):8235–8244PubMedPubMedCentralGoogle Scholar
  64. 64.
    Davis MD, Wonderling RS, Walker SL, Owens RA (1999) Analysis of the effects of charge cluster mutations in adeno-associated virus Rep68 protein in vitro. J Virol 73(3):2084–2093PubMedPubMedCentralGoogle Scholar
  65. 65.
    Xiao X, Xiao W, Li J, Samulski RJ (1997) A novel 165-base-pair terminal repeat sequence is the sole cis requirement for the adeno-associated virus life cycle. J Virol 71(2):941–948PubMedPubMedCentralGoogle Scholar
  66. 66.
    Wang XS, Ponnazhagan S, Srivastava A (1996) Rescue and replication of adeno-associated virus type 2 as well as vector DNA sequences from recombinant plasmids containing deletions in the viral inverted terminal repeats: selective encapsidation of viral genomes in progeny virions. J Virol 70(3):1668–1677PubMedPubMedCentralGoogle Scholar
  67. 67.
    Wang XS, Ponnazhagan S, Srivastava A (1995) Rescue and replication signals of the adeno-associated virus 2 genome. J Mol Biol 250(5):573–580. doi: 10.1006/jmbi.1995.0398 PubMedGoogle Scholar
  68. 68.
    Wang XS, Srivastava A (1997) A novel terminal resolution-like site in the adeno-associated virus type 2 genome. J Virol 71(2):1140–1146PubMedPubMedCentralGoogle Scholar
  69. 69.
    Wang XS, Qing K, Ponnazhagan S, Srivastava A (1997) Adeno-associated virus type 2 DNA replication in vivo: mutation analyses of the D sequence in viral inverted terminal repeats. J Virol 71(4):3077–3082PubMedPubMedCentralGoogle Scholar
  70. 70.
    Chiorini JA, Weitzman MD, Owens RA, Urcelay E, Safer B, Kotin RM (1994) Biologically active Rep proteins of adeno-associated virus type 2 produced as fusion proteins in Escherichia coli. J Virol 68(2):797–804PubMedPubMedCentralGoogle Scholar
  71. 71.
    Zhou X, Zolotukhin I, Im DS, Muzyczka N (1999) Biochemical characterization of adeno-associated virus rep68 DNA helicase and ATPase activities. J Virol 73(2):1580–1590PubMedPubMedCentralGoogle Scholar
  72. 72.
    Brister JR, Muzyczka N (2000) Mechanism of Rep-mediated adeno-associated virus origin nicking. J Virol 74(17):7762–7771PubMedPubMedCentralGoogle Scholar
  73. 73.
    Smith RH, Kotin RM (1998) The Rep52 gene product of adeno-associated virus is a DNA helicase with 3′-to-5′ polarity. J Virol 72(6):4874–4881PubMedPubMedCentralGoogle Scholar
  74. 74.
    Im DS, Muzyczka N (1992) Partial purification of adeno-associated virus Rep78, Rep52, and Rep40 and their biochemical characterization. J Virol 66(2):1119–1128PubMedPubMedCentralGoogle Scholar
  75. 75.
    Collaco RF, Kalman-Maltese V, Smith AD, Dignam JD, Trempe JP (2003) A biochemical characterization of the adeno-associated virus Rep40 helicase. J Biol Chem 278(36):34011–34017. doi: 10.1074/jbc.M301537200 PubMedGoogle Scholar
  76. 76.
    Dignam SS, Collaco RF, Bieszczad J, Needham P, Trempe JP, Dignam JD (2007) Coupled ATP and DNA binding of adeno-associated virus Rep40 helicase. Biochemistry 46(2):568–576. doi: 10.1021/bi061762v PubMedGoogle Scholar
  77. 77.
    Kohlbrenner E, Aslanidi G, Nash K, Shklyaev S, Campbell-Thompson M, Byrne BJ, Snyder RO, Muzyczka N, Warrington KH Jr, Zolotukhin S (2005) Successful production of pseudotyped rAAV vectors using a modified baculovirus expression system. Mol Ther 12(6):1217–1225. doi: 10.1016/j.ymthe.2005.08.018 PubMedPubMedCentralGoogle Scholar
  78. 78.
    Popa-Wagner R, Porwal M, Kann M, Reuss M, Weimer M, Florin L, Kleinschmidt JA (2012) Impact of VP1-specific protein sequence motifs on adeno-associated virus type 2 intracellular trafficking and nuclear entry. J Virol 86(17):9163–9174. doi: 10.1128/JVI.00282-12 PubMedPubMedCentralGoogle Scholar
  79. 79.
    Girod A, Wobus CE, Zadori Z, Ried M, Leike K, Tijssen P, Kleinschmidt JA, Hallek M (2002) The VP1 capsid protein of adeno-associated virus type 2 is carrying a phospholipase A2 domain required for virus infectivity. J Gen Virol 83(Pt 5):973–978PubMedGoogle Scholar
  80. 80.
    Laughlin CA, Tratschin JD, Coon H, Carter BJ (1983) Cloning of infectious adeno-associated virus genomes in bacterial plasmids. Gene 23(1):65–73PubMedGoogle Scholar
  81. 81.
    Hermonat PL, Muzyczka N (1984) Use of adeno-associated virus as a mammalian DNA cloning vector: transduction of neomycin resistance into mammalian tissue culture cells. Proc Natl Acad Sci 81(20):6466–6470PubMedPubMedCentralGoogle Scholar
  82. 82.
    Samulski RJ, Chang LS, Shenk T (1989) Helper-free stocks of recombinant adeno-associated viruses: normal integration does not require viral gene expression. J Virol 63(9):3822–3828PubMedPubMedCentralGoogle Scholar
  83. 83.
    McLaughlin SK, Collis P, Hermonat PL, Muzyczka N (1988) Adeno-associated virus general transduction vectors: analysis of proviral structures. J Virol 62(6):1963–1973PubMedPubMedCentralGoogle Scholar
  84. 84.
    Buller RM, Janik JE, Sebring ED, Rose JA (1981) Herpes simplex virus types 1 and 2 completely help adenovirus-associated virus replication. J Virol 40(1):241–247PubMedPubMedCentralGoogle Scholar
  85. 85.
    Grimm D, Kleinschmidt JA (1999) Progress in adeno-associated virus type 2 vector production: promises and prospects for clinical use. Hum Gene Ther 10(15):2445–2450. doi: 10.1089/10430349950016799 PubMedGoogle Scholar
  86. 86.
    Ferrari FK, Samulski T, Shenk T, Samulski RJ (1996) Second-strand synthesis is a rate-limiting step for efficient transduction by recombinant adeno-associated virus vectors. J Virol 70(5):3227–3234PubMedPubMedCentralGoogle Scholar
  87. 87.
    Ferrari FK, Xiao X, McCarty D, Samulski RJ (1997) New developments in the generation of Ad-free, high-titer rAAV gene therapy vectors. Nat Med 3(11):1295–1297PubMedGoogle Scholar
  88. 88.
    Xiao X, Li J, Samulski RJ (1998) Production of high-titer recombinant adeno-associated virus vectors in the absence of helper adenovirus. J Virol 72(3):2224–2232PubMedPubMedCentralGoogle Scholar
  89. 89.
    Salvetti A, Oreve S, Chadeuf G, Favre D, Cherel Y, Champion-Arnaud P, David-Ameline J, Moullier P (1998) Factors influencing recombinant adeno-associated virus production. Hum Gene Ther 9(5):695–706. doi: 10.1089/hum.1998.9.5-695 PubMedGoogle Scholar
  90. 90.
    Matsushita T, Elliger S, Elliger C, Podsakoff G, Villarreal L, Kurtzman GJ, Iwaki Y, Colosi P (1998) Adeno-associated virus vectors can be efficiently produced without helper virus. Gene Ther 5(7):938–945. doi: 10.1038/ PubMedGoogle Scholar
  91. 91.
    Grimm D, Kern A, Rittner K, Kleinschmidt JA (1998) Novel tools for production and purification of recombinant adenoassociated virus vectors. Hum Gene Ther 9(18):2745–2760. doi: 10.1089/hum.1998.9.18-2745 PubMedGoogle Scholar
  92. 92.
    Galibert L, Merten OW (2011) Latest developments in the large-scale production of adeno-associated virus vectors in insect cells toward the treatment of neuromuscular diseases. J Invertebr Pathol 107(Suppl):S80–S93. doi: 10.1016/j.jip.2011.05.008 PubMedGoogle Scholar
  93. 93.
    Li J, Samulski RJ, Xiao X (1997) Role for highly regulated rep gene expression in adeno-associated virus vector production. J Virol 71(7):5236–5243PubMedPubMedCentralGoogle Scholar
  94. 94.
    Collaco RF, Cao X, Trempe JP (1999) A helper virus-free packaging system for recombinant adeno-associated virus vectors. Gene 238(2):397–405PubMedGoogle Scholar
  95. 95.
    Rabinowitz JE, Rolling F, Li C, Conrath H, Xiao W, Xiao X, Samulski RJ (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(2):791–801PubMedPubMedCentralGoogle Scholar
  96. 96.
    Cecchini S, Negrete A, Kotin RM (2008) Toward exascale production of recombinant adeno-associated virus for gene transfer applications. Gene Ther 15(11):823–830. doi: 10.1038/gt.2008.61 PubMedGoogle Scholar
  97. 97.
    Yang Q, Chen F, Trempe JP (1994) Characterization of cell lines that inducibly express the adeno-associated virus Rep proteins. J Virol 68(8):4847–4856PubMedPubMedCentralGoogle Scholar
  98. 98.
    Caillet-Fauquet P, Perros M, Brandenburger A, Spegelaere P, Rommelaere J (1990) Programmed killing of human cells by means of an inducible clone of parvoviral genes encoding non-structural proteins. EMBO J 9(9):2989–2995PubMedPubMedCentralGoogle Scholar
  99. 99.
    Clark KR, Voulgaropoulou F, Fraley DM, Johnson PR (1995) Cell lines for the production of recombinant adeno-associated virus. Hum Gene Ther 6(10):1329–1341. doi: 10.1089/hum.1995.6.10-1329 PubMedGoogle Scholar
  100. 100.
    Flotte TR, Barraza-Ortiz X, Solow R, Afione SA, Carter BJ, Guggino WB (1995) An improved system for packaging recombinant adeno-associated virus vectors capable of in vivo transduction. Gene Ther 2(1):29–37PubMedGoogle Scholar
  101. 101.
    Tamayose K, Hirai Y, Shimada T (1996) A new strategy for large-scale preparation of high-titer recombinant adeno-associated virus vectors by using packaging cell lines and sulfonated cellulose column chromatography. Hum Gene Ther 7(4):507–513. doi: 10.1089/hum.1996.7.4-507 PubMedGoogle Scholar
  102. 102.
    Gao GP, Qu G, Faust LZ, Engdahl RK, Xiao W, Hughes JV, Zoltick PW, Wilson JM (1998) High-titer adeno-associated viral vectors from a Rep/Cap cell line and hybrid shuttle virus. Hum Gene Ther 9(16):2353–2362. doi: 10.1089/hum.1998.9.16-2353 PubMedGoogle Scholar
  103. 103.
    Fan PD, Dong JY (1997) Replication of rep-cap genes is essential for the high-efficiency production of recombinant AAV. Hum Gene Ther 8(1):87–98. doi: 10.1089/hum.1997.8.1-87 PubMedGoogle Scholar
  104. 104.
    Inoue N, Russell DW (1998) Packaging cells based on inducible gene amplification for the production of adeno-associated virus vectors. J Virol 72(9):7024–7031PubMedPubMedCentralGoogle Scholar
  105. 105.
    Chadeuf G, Favre D, Tessier J, Provost N, Nony P, Kleinschmidt J, Moullier P, Salvetti A (2000) Efficient recombinant adeno-associated virus production by a stable rep-cap HeLa cell line correlates with adenovirus-induced amplification of the integrated rep-cap genome. J Gene Med 2(4):260–268PubMedGoogle Scholar
  106. 106.
    Gao GP, Lu F, Sanmiguel JC, Tran PT, Abbas Z, Lynd KS, Marsh J, Spinner NB, Wilson JM (2002) Rep/Cap gene amplification and high-yield production of AAV in an A549 cell line expressing Rep/Cap. Mol Ther 5(5 Pt 1):644–649. doi: 10.1006/mthe.2001.0591 PubMedGoogle Scholar
  107. 107.
    Qiao C, Li J, Skold A, Zhang X, Xiao X (2002) Feasibility of generating adeno-associated virus packaging cell lines containing inducible adenovirus helper genes. J Virol 76(4):1904–1913PubMedPubMedCentralGoogle Scholar
  108. 108.
    Blouin V, Brument N, Toublanc E, Raimbaud I, Moullier P, Salvetti A (2004) Improving rAAV production and purification: towards the definition of a scaleable process. J Gene Med 6(Suppl 1):S223–S228. doi: 10.1002/jgm.505 PubMedGoogle Scholar
  109. 109.
    Farson D, Harding TC, Tao L, Liu J, Powell S, Vimal V, Yendluri S, Koprivnikar K, Ho K, Twitty C, Husak P, Lin A, Snyder RO, Donahue BA (2004) Development and characterization of a cell line for large-scale, serum-free production of recombinant adeno-associated viral vectors. J Gene Med 6(12):1369–1381. doi: 10.1002/jgm.622 PubMedGoogle Scholar
  110. 110.
    E1A and E1B Yuan Z, Qiao C, Hu P, Li J, Xiao X (2011) A versatile adeno-associated virus vector producer cell line method for scalable vector production of different serotypes. Hum Gene Ther 22(5):613–624. doi: 10.1089/hum.2010.241
  111. 111.
    Weindler FW, Heilbronn R (1991) A subset of herpes simplex virus replication genes provides helper functions for productive adeno-associated virus replication. J Virol 65(5):2476–2483PubMedPubMedCentralGoogle Scholar
  112. 112.
    Weitzman MD, Fisher KJ, Wilson JM (1996) Recruitment of wild-type and recombinant adeno-associated virus into adenovirus replication centers. J Virol 70(3):1845–1854PubMedPubMedCentralGoogle Scholar
  113. 113.
    Conway JE, Zolotukhin S, Muzyczka N, Hayward GS, Byrne BJ (1997) Recombinant adeno-associated virus type 2 replication and packaging is entirely supported by a herpes simplex virus type 1 amplicon expressing Rep and Cap. J Virol 71(11):8780–8789PubMedPubMedCentralGoogle Scholar
  114. 114.
    Clement N, Knop DR, Byrne BJ (2009) Large-scale adeno-associated viral vector production using a herpesvirus-based system enables manufacturing for clinical studies. Hum Gene Ther 20(8):796–806. doi: 10.1089/hum.2009.094 PubMedPubMedCentralGoogle Scholar
  115. 115.
    Conway JE, Rhys CM, Zolotukhin I, Zolotukhin S, Muzyczka N, Hayward GS, Byrne BJ (1999) High-titer recombinant adeno-associated virus production utilizing a recombinant herpes simplex virus type I vector expressing AAV-2 Rep and Cap. Gene Ther 6(6):986–993. doi: 10.1038/ PubMedGoogle Scholar
  116. 116.
    Feudner E, de Alwis M, Thrasher AJ, Ali RR, Fauser S (2001) Optimization of recombinant adeno-associated virus production using an herpes simplex virus amplicon system. J Virol Methods 96(2):97–105PubMedGoogle Scholar
  117. 117.
    Booth MJ, Mistry A, Li X, Thrasher A, Coffin RS (2004) Transfection-free and scalable recombinant AAV vector production using HSV/AAV hybrids. Gene Ther 11(10):829–837. doi: 10.1038/ PubMedGoogle Scholar
  118. 118.
    Kang W, Wang L, Harrell H, Liu J, Thomas DL, Mayfield TL, Scotti MM, Ye GJ, Veres G, Knop DR (2009) An efficient rHSV-based complementation system for the production of multiple rAAV vector serotypes. Gene Ther 16(2):229–239. doi: 10.1038/gt.2008.158 PubMedGoogle Scholar
  119. 119.
    Thomas DL, Wang L, Niamke J, Liu J, Kang W, Scotti MM, Ye GJ, Veres G, Knop DR (2009) Scalable recombinant adeno-associated virus production using recombinant herpes simplex virus type 1 coinfection of suspension-adapted mammalian cells. Hum Gene Ther 20(8):861–870. doi: 10.1089/hum.2009.004 PubMedGoogle Scholar
  120. 120.
    van Oers MM (2011) Opportunities and challenges for the baculovirus expression system. J Invertebr Pathol 107(Suppl):S3–S15. doi: 10.1016/j.jip.2011.05.001 PubMedGoogle Scholar
  121. 121.
    Urabe M, Ding C, Kotin RM (2002) Insect cells as a factory to produce adeno-associated virus type 2 vectors. Hum Gene Ther 13(16):1935–1943. doi: 10.1089/10430340260355347 PubMedGoogle Scholar
  122. 122.
    Owens RA, Trempe JP, Chejanovsky N, Carter BJ (1991) Adeno-associated virus rep proteins produced in insect and mammalian expression systems: wild-type and dominant-negative mutant proteins bind to the viral replication origin. Virology 184(1):14–22PubMedGoogle Scholar
  123. 123.
    Ruffing M, Zentgraf H, Kleinschmidt JA (1992) Assembly of viruslike particles by recombinant structural proteins of adeno-associated virus type 2 in insect cells. J Virol 66(12):6922–6930PubMedPubMedCentralGoogle Scholar
  124. 124.
    Palombo F, Monciotti A, Recchia A, Cortese R, Ciliberto G, La Monica N (1998) Site-specific integration in mammalian cells mediated by a new hybrid baculovirus-adeno-associated virus vector. J Virol 72(6):5025–5034PubMedPubMedCentralGoogle Scholar
  125. 125.
    Chen H (2008) Intron splicing-mediated expression of AAV Rep and Cap genes and production of AAV vectors in insect cells. Mol Ther J Am Soc Gene Ther 16(5):924–930. doi: 10.1038/mt.2008.35 Google Scholar
  126. 126.
    Negrete A, Yang LC, Mendez AF, Levy JR, Kotin RM (2007) Economized large-scale production of high yield of rAAV for gene therapy applications exploiting baculovirus expression system. J Gene Med 9(11):938–948. doi: 10.1002/jgm.1092 PubMedGoogle Scholar
  127. 127.
    Negrete A, Kotin RM (2009) Production of recombinant adeno-associated vectors using two bioreactor configurations at different scales. J Virol Methods 145(2):155–161. doi: 10.1016/j.jviromet.2007.05.020 Google Scholar
  128. 128.
    Smith RH, Levy JR, Kotin RM (2009) A simplified baculovirus-AAV expression vector system coupled with one-step affinity purification yields high-titer rAAV stocks from insect cells. Mol Ther 17(11):1888–1896. doi: 10.1038/mt.2009.128 PubMedPubMedCentralGoogle Scholar
  129. 129.
    Virag T, Cecchini S, Kotin RM (2009) Producing recombinant adeno-associated virus in foster cells: overcoming production limitations using a baculovirus-insect cell expression strategy. Hum Gene Ther 20(8):807–817. doi: 10.1089/hum.2009.092 PubMedPubMedCentralGoogle Scholar
  130. 130.
    Aslanidi G, Lamb K, Zolotukhin S (2009) An inducible system for highly efficient production of recombinant adeno-associated virus (rAAV) vectors in insect Sf9 cells. Proc Natl Acad Sci U S A 106(13):5059–5064. doi: 10.1073/pnas.0810614106 PubMedPubMedCentralGoogle Scholar
  131. 131.
    Huang KS, Lo WH, Chung YC, Lai YK, Chen CY, Chou ST, Hu YC (2007) Combination of baculovirus-mediated gene delivery and packed-bed reactor for scalable production of adeno-associated virus. Hum Gene Ther 18(11):1161–1170. doi: 10.1089/hum.2007.107 PubMedGoogle Scholar
  132. 132.
    Meghrous J, Aucoin MG, Jacob D, Chahal PS, Arcand N, Kamen AA (2005) Production of recombinant adeno-associated viral vectors using a baculovirus/insect cell suspension culture system: from shake flasks to a 20-L bioreactor. Biotechnol Prog 21(1):154–160. doi: 10.1021/bp049802e PubMedGoogle Scholar
  133. 133.
    Cecchini S, Virag T, Kotin RM (2011) Reproducible high yields of recombinant adeno-associated virus produced using invertebrate cells in 0.02- to 200-liter cultures. Hum Gene Ther 22(8):1021–1030. doi: 10.1089/hum.2010.250 PubMedPubMedCentralGoogle Scholar
  134. 134.
    Aucoin MG, Perrier M, Kamen AA (2006) Production of adeno-associated viral vectors in insect cells using triple infection: optimization of baculovirus concentration ratios. Biotechnol Bioeng 95(6):1081–1092. doi: 10.1002/bit.21069 PubMedGoogle Scholar
  135. 135.
    Mena JA, Aucoin MG, Montes J, Chahal PS, Kamen AA (2010) Improving adeno-associated vector yield in high density insect cell cultures. J Gene Med 12(2):157–167. doi: 10.1002/jgm.1420 PubMedGoogle Scholar
  136. 136.
    Aucoin MG, Perrier M, Kamen AA (2007) Improving AAV vector yield in insect cells by modulating the temperature after infection. Biotechnol Bioeng 97(6):1501–1509. doi: 10.1002/bit.21364 PubMedGoogle Scholar
  137. 137.
    Wagner JA, Moran ML, Messner AH, Daifuku R, Conrad CK, Reynolds T, Guggino WB, Moss RB, Carter BJ, Wine JJ, Flotte TR, Gardner P (1998) A phase I/II study of tgAAV-CF for the treatment of chronic sinusitis in patients with cystic fibrosis. Hum Gene Ther 9(6):889–909. doi: 10.1089/hum.1998.9.6-889 PubMedGoogle Scholar
  138. 138.
    Aitken ML, Moss RB, Waltz DA, Dovey ME, Tonelli MR, McNamara SC, Gibson RL, Ramsey BW, Carter BJ, Reynolds TC (2001) A phase I study of aerosolized administration of tgAAVCF to cystic fibrosis subjects with mild lung disease. Hum Gene Ther 12(15):1907–1916. doi: 10.1089/104303401753153956 PubMedGoogle Scholar
  139. 139.
    Kay MA, Manno CS, Ragni MV, Larson PJ, Couto LB, McClelland A, Glader B, Chew AJ, Tai SJ, Herzog RW, Arruda V, Johnson F, Scallan C, Skarsgard E, Flake AW, High KA (2000) Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector. Nat Genet 24(3):257–261. doi: 10.1038/73464 PubMedGoogle Scholar
  140. 140.
    Yarborough M, Sharp RR (2009) Public trust and research a decade later: what have we learned since Jesse Gelsinger’s death? Mol Genet Metab 97(1):4–5. doi: 10.1016/j.ymgme.2009.02.002 PubMedGoogle Scholar
  141. 141.
    Maguire AM, Simonelli F, Pierce EA, Pugh EN Jr, Mingozzi F, Bennicelli J, Banfi S, Marshall KA, Testa F, Surace EM, Rossi S, Lyubarsky A, Arruda VR, Konkle B, Stone E, Sun J, Jacobs J, Dell’Osso L, Hertle R, Ma JX, Redmond TM, Zhu X, Hauck B, Zelenaia O, Shindler KS, Maguire MG, Wright JF, Volpe NJ, McDonnell JW, Auricchio A, High KA, Bennett J (2008) Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med 358(21):2240–2248. doi: 10.1056/NEJMoa0802315 PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  • Konstantina Grosios
    • 1
    Email author
  • Harald Petry
    • 1
  • Jacek Lubelski
    • 1
  1. 1.uniQure B.VAmsterdamThe Netherlands

Personalised recommendations