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Adeno-Associated Vectors for Gene Delivery to the Nervous System

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Gene Delivery and Therapy for Neurological Disorders

Part of the book series: Neuromethods ((NM,volume 98))

Abstract

Gene therapy approaches based on adeno-associated viral vector (AAV) systems offer many unique advantages for nervous system applications. These vectors are opening up new approaches for the treatment of neurodegenerative diseases. AAV can efficiently deliver genes to postmitotic neuronal cell types offering long-term expression, can be generated in high titers, and are associated with only minimal immunological complications. Numerous animal studies have demonstrated the efficiency of these vectors both at preclinical and clinical development stages. The current chapter will describe the basic features of AAV vectors, list few examples of their applications as a therapeutic tool to treat diseases of the central nervous system, and discuss progress in the manufacturing process.

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References

  1. Terzi D, Zachariou V (2008) Adeno-associated virus-mediated gene delivery approaches for the treatment of CNS disorders. Biotechnol J 3(12):1555–1563. doi:10.1002/biot.200800284

    Article  CAS  PubMed  Google Scholar 

  2. Gray SJ (2013) Gene therapy and neurodevelopmental disorders. Neuropharmacology 68:136. doi:10.1016/j.neuropharm.2012.06.024

    Article  CAS  PubMed  Google Scholar 

  3. Wanisch K, Yanez-Munoz RJ (2009) Integration-deficient lentiviral vectors: a slow coming of age. Mol Ther 17(8):1316–1332. doi:10.1038/mt.2009.122

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Lentz TB, Gray SJ, Samulski RJ (2012) Viral vectors for gene delivery to the central nervous system. Neurobiol Dis 48(2):179–188. doi:10.1016/j.nbd.2011.09.014

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Binny CJ, Nathwani AC (2012) Vector systems for prenatal gene therapy: principles of adeno-associated virus vector design and production. Methods Mol Biol 891:109–131. doi:10.1007/978-1-61779-873-3_6

    CAS  PubMed  Google Scholar 

  6. Morahan JM, Yu B, Trent RJ, Pamphlett R (2007) A gene-environment study of the paraoxonase 1 gene and pesticides in amyotrophic lateral sclerosis. Neurotoxicology 28(3):532–540. doi:10.1016/j.neuro.2006.11.007

    Article  CAS  PubMed  Google Scholar 

  7. Le Bec C, Douar AM (2006) Gene therapy progress and prospects–vectorology: design and production of expression cassettes in AAV vectors. Gene Ther 13(10):805–813. doi:10.1038/sj.gt.3302724

    PubMed  Google Scholar 

  8. Leone P, Shera D, McPhee SW, Francis JS, Kolodny EH, Bilaniuk LT, Wang DJ, Assadi M, Goldfarb O, Goldman HW, Freese A, Young D, During MJ, Samulski RJ, Janson CG (2012) Long-term follow-up after gene therapy for canavan disease. Sci Transl Med 4(165):165ra163. doi:10.1126/scitranslmed.3003454

    PubMed Central  PubMed  Google Scholar 

  9. 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Simonelli F, Maguire AM, Testa F, Pierce EA, Mingozzi F, Bennicelli JL, Rossi S, Marshall K, Banfi S, Surace EM, Sun J, Redmond TM, Zhu X, Shindler KS, Ying GS, Ziviello C, Acerra C, Wright JF, McDonnell JW, High KA, Bennett J, Auricchio A (2010) Gene therapy for Leber’s congenital amaurosis is safe and effective through 1.5 years after vector administration. Mol Ther 18(3):643–650. doi:10.1038/mt.2009.277

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Yla-Herttuala S (2012) Endgame: glybera finally recommended for approval as the first gene therapy drug in the European union. Mol Ther 20(10):1831–1832. doi:10.1038/mt.2012.194

    Article  PubMed Central  PubMed  Google Scholar 

  12. Miller N (2012) Glybera and the future of gene therapy in the European Union. Nat Rev Drug Discov 11(5):419

    Article  CAS  PubMed  Google Scholar 

  13. Halbert CL, Miller AD, McNamara S, Emerson J, Gibson RL, Ramsey B, Aitken ML (2006) Prevalence of neutralizing antibodies against adeno-associated virus (AAV) types 2, 5, and 6 in cystic fibrosis and normal populations: implications for gene therapy using AAV vectors. Hum Gene Ther 17(4):440–447. doi:10.1089/hum.2006.17.440

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Binny C, McIntosh J, Della Peruta M, Kymalainen H, Tuddenham EG, Buckley SM, Waddington SN, McVey JH, Spence Y, Morton CL, Thrasher AJ, Gray JT, Castellino FJ, Tarantal AF, Davidoff AM, Nathwani AC (2012) AAV-mediated gene transfer in the perinatal period results in expression of FVII at levels that protect against fatal spontaneous hemorrhage. Blood 119(4):957–966. doi:10.1182/blood-2011-09-377630

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Aalbers CJ, Tak PP, Vervoordeldonk MJ (2011) Advancements in adeno-associated viral gene therapy approaches: exploring a new horizon. F1000 Med Rep 3:17. doi:10.3410/m3-17

    Article  PubMed Central  PubMed  Google Scholar 

  16. Choi VW, McCarty DM, Samulski RJ (2005) AAV hybrid serotypes: improved vectors for gene delivery. Curr Gene Ther 5(3):299–310

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Gao G, Zhong L, Danos O (2011) Exploiting natural diversity of AAV for the design of vectors with novel properties. Methods Mol Biol 807:93–118. doi:10.1007/978-1-61779-370-7_4

    Article  CAS  PubMed  Google Scholar 

  18. Harbison CE, Weichert WS, Gurda BL, Chiorini JA, Agbandje-McKenna M, Parrish CR (2012) Examining the cross-reactivity and neutralization mechanisms of a panel of mAbs against adeno-associated virus serotypes 1 and 5. J Gen Virol 93(Pt 2):347–355. doi:10.1099/vir. 0.035113-0

    Google Scholar 

  19. Wu Z, Asokan A, Grieger JC, Govindasamy L, Agbandje-McKenna M, Samulski RJ (2006) Single amino acid changes can influence titer, heparin binding, and tissue tropism in different adeno-associated virus serotypes. J Virol 80(22):11393–11397. doi:10.1128/jvi. 01288-06

    Google Scholar 

  20. Zincarelli C, Soltys S, Rengo G, Rabinowitz JE (2008) Analysis of AAV serotypes 1-9 mediated gene expression and tropism in mice after systemic injection. Mol Ther 16(6):1073–1080. doi:10.1038/mt.2008.76

    Article  CAS  PubMed  Google Scholar 

  21. Cearley CN, Vandenberghe LH, Parente MK, Carnish ER, Wilson JM, Wolfe JH (2008) Expanded repertoire of AAV vector serotypes mediate unique patterns of transduction in mouse brain. Mol Ther 16(10):1710–1718. doi:10.1038/mt.2008.166

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Dane AP, Wowro SJ, Cunningham SC, Alexander IE (2013) Comparison of gene transfer to the murine liver following intraperitoneal and intraportal delivery of hepatotropic AAV pseudo-serotypes. Gene Ther 20:460. doi:10.1038/gt.2012.67

    Article  CAS  PubMed  Google Scholar 

  23. Baba Y, Satoh S, Otsu M, Sasaki E, Okada T, Watanabe S (2012) In vitro cell subtype-specific transduction of adeno-associated virus in mouse and marmoset retinal explant culture. Biochimie 94(12):2716–2722. doi:10.1016/j.biochi.2012.08.010

    Article  CAS  PubMed  Google Scholar 

  24. Dane AP, Cunningham SC, Graf NS, Alexander IE (2009) Sexually dimorphic patterns of episomal rAAV genome persistence in the adult mouse liver and correlation with hepatocellular proliferation. Mol Ther 17(9):1548–1554. doi:10.1038/mt.2009.139

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Nathwani AC, Cochrane M, McIntosh J, Ng CY, Zhou J, Gray JT, Davidoff AM (2009) Enhancing transduction of the liver by adeno-associated viral vectors. Gene Ther 16(1):60–69. doi:10.1038/gt.2008.137

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Boutin S, Monteilhet V, Veron P, Leborgne C, Benveniste O, Montus MF, Masurier C (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(6):704–712. doi:10.1089/hum.2009.182

    Article  CAS  PubMed  Google Scholar 

  27. 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. McIntosh JH, Cochrane M, Cobbold S, Waldmann H, Nathwani SA, Davidoff AM, Nathwani AC (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(1):78–85. doi:10.1038/gt.2011.64

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Asokan A, Conway JC, Phillips JL, Li C, Hegge J, Sinnott R, Yadav S, DiPrimio N, Nam HJ, Agbandje-McKenna M, McPhee S, Wolff J, Samulski RJ (2010) Reengineering a receptor footprint of adeno-associated virus enables selective and systemic gene transfer to muscle. Nat Biotechnol 28(1):79–82. doi:10.1038/nbt.1599

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Gray SJ, Blake BL, Criswell HE, Nicolson SC, Samulski RJ, McCown TJ, Li W (2010) Directed evolution of a novel adeno-associated virus (AAV) vector that crosses the seizure-compromised blood-brain barrier (BBB). Mol Ther 18(3):570–578. doi:10.1038/mt.2009.292

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Grimm D, Lee JS, Wang L, Desai T, Akache B, Storm TA, Kay MA (2008) In vitro and in vivo gene therapy vector evolution via multispecies interbreeding and retargeting of adeno-associated viruses. J Virol 82(12):5887–5911. doi:10.1128/jvi. 00254-08

    Google Scholar 

  32. Allocca M, Doria M, Petrillo M, Colella P, Garcia-Hoyos M, Gibbs D, Kim SR, Maguire A, Rex TS, Di Vicino U, Cutillo L, Sparrow JR, Williams DS, Bennett J, Auricchio A (2008) Serotype-dependent packaging of large genes in adeno-associated viral vectors results in effective gene delivery in mice. J Clin Invest 118(5):1955–1964. doi:10.1172/jci34316

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Wu Z, Yang H, Colosi P (2010) Effect of genome size on AAV vector packaging. Mol Ther 18(1):80–86. doi:10.1038/mt.2009.255

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Dong B, Nakai H, Xiao W (2010) Characterization of genome integrity for oversized recombinant AAV vector. Mol Ther 18(1):87–92. doi:10.1038/mt.2009.258

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Lai Y, Yue Y, Duan D (2010) Evidence for the failure of adeno-associated virus serotype 5 to package a viral genome > or =8.2 kb. Mol Ther 18(1):75–79. doi:10.1038/mt.2009.256

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Grose WE, Clark KR, Griffin D, Malik V, Shontz KM, Montgomery CL, Lewis S, Brown RH Jr, Janssen PM, Mendell JR, Rodino-Klapac LR (2012) Homologous recombination mediates functional recovery of dysferlin deficiency following AAV5 gene transfer. PLoS One 7(6):e39233. doi:10.1371/journal.pone.0039233

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Nathwani AC, Gray JT, Ng CY, Zhou J, Spence Y, Waddington SN, Tuddenham EG, Kemball-Cook G, McIntosh J, Boon-Spijker M, Mertens K, Davidoff AM (2006) 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(7):2653–2661. doi:10.1182/blood-2005-10-4035

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Li H, Haurigot V, Doyon Y, Li T, Wong SY, Bhagwat AS, Malani N, Anguela XM, Sharma R, Ivanciu L, Murphy SL, Finn JD, Khazi FR, Zhou S, Paschon DE, Rebar EJ, Bushman FD, Gregory PD, Holmes MC, High KA (2011) In vivo genome editing restores haemostasis in a mouse model of haemophilia. Nature 475(7355):217–221. doi:10.1038/nature10177

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Wang Z, Lisowski L, Finegold MJ, Nakai H, Kay MA, Grompe M (2012) AAV vectors containing rDNA homology display increased chromosomal integration and transgene persistence. Mol Ther 20(10):1902–1911. doi:10.1038/mt.2012.157

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Argyros O, Wong SP, Fedonidis C, Tolmachov O, Waddington SN, Howe SJ, Niceta M, Coutelle C, Harbottle RP (2011) Development of S/MAR minicircles for enhanced and persistent transgene expression in the mouse liver. J Mol Med (Berl) 89(5):515–529. doi:10.1007/s00109-010-0713-3

    Article  CAS  Google Scholar 

  42. Miller JC, Tan S, Qiao G, Barlow KA, Wang J, Xia DF, Meng X, Paschon DE, Leung E, Hinkley SJ, Dulay GP, Hua KL, Ankoudinova I, Cost GJ, Urnov FD, Zhang HS, Holmes MC, Zhang L, Gregory PD, Rebar EJ (2011) A TALE nuclease architecture for efficient genome editing. Nat Biotechnol 29(2):143–148. doi:10.1038/nbt.1755

    Article  CAS  PubMed  Google Scholar 

  43. Lock M, Alvira M, Vandenberghe LH, Samanta A, Toelen J, Debyser Z, Wilson JM (2010) Rapid, simple, and versatile manufacturing of recombinant adeno-associated viral vectors at scale. Hum Gene Ther 21(10):1259–1271. doi:10.1089/hum.2010.055

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Zolotukhin S, Byrne BJ, Mason E, Zolotukhin I, Potter M, Chesnut K, Summerford C, Samulski RJ, Muzyczka N (1999) Recombinant adeno-associated virus purification using novel methods improves infectious titer and yield. Gene Ther 6(6):973–985. doi:10.1038/sj.gt.3300938

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

M.A. and P.J.M. are supported by ERC Advanced Investigator Award.

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Authors and Affiliations

  1. Department of Neuroscience, Sheffield Institute for Translational Neuroscience, University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK

    Pádraig J. Mulcahy, Christopher Binny, Bartosz Muszynski, Evangelia Karyka & Mimoun Azzouz

  2. Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia

    Mimoun Azzouz

Authors
  1. Pádraig J. Mulcahy
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  2. Christopher Binny
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  3. Bartosz Muszynski
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  4. Evangelia Karyka
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  5. Mimoun Azzouz
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Corresponding author

Correspondence to Mimoun Azzouz .

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Editors and Affiliations

  1. Queen Mary University of London, London, United Kingdom

    Xuenong Bo

  2. Netherlands Institute for Neuroscience, Amsterdam, The Netherlands

    Joost Verhaagen

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Mulcahy, P.J., Binny, C., Muszynski, B., Karyka, E., Azzouz, M. (2015). Adeno-Associated Vectors for Gene Delivery to the Nervous System. In: Bo, X., Verhaagen, J. (eds) Gene Delivery and Therapy for Neurological Disorders. Neuromethods, vol 98. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-2306-9_1

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  • DOI: https://doi.org/10.1007/978-1-4939-2306-9_1

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  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-2305-2

  • Online ISBN: 978-1-4939-2306-9

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