Skip to main content

Subpial AAV Delivery for Spinal Parenchymal Gene Regulation in Adult Mammals

Part of the Methods in Molecular Biology book series (MIMB,volume 1950)

Abstract

The use of adeno-associated virus (AAV) vectors has become an attractive method for treatment of a variety of neurodegenerative disorders by permitting targeted gene upregulation or silencing in the CNS. Systemic and intrathecal infusion, while preferable routes of vector delivery, have shown encouraging but variable efficacy due to the poor permeability of AAV into spinal cord and brain parenchyma in adult mammals. Recently we have developed a novel and relatively noninvasive technique of spinal subpial vector delivery. This technique confers widespread transgene expression throughout the spinal parenchyma, including both white and gray matter. We have demonstrated that this technique can be performed safely, with a high level of accuracy, and is effective in both small (mouse or rat) and large preclinical (adult pig or nonhuman primate) animal models. In this chapter we provide a comprehensive description of the subpial vector delivery technique in adult rodents (mouse and rat) and large preclinical animals (adult pig and nonhuman primates).

Key words

  • Subpial delivery
  • Gene therapy
  • Mice
  • Rats
  • Pigs
  • Nonhuman primates
  • Adeno-associated virus
  • Spinal cord

This is a preview of subscription content, access via your institution.

Buying options

Protocol
USD   49.95
Price excludes VAT (USA)
  • DOI: 10.1007/978-1-4939-9139-6_12
  • Chapter length: 25 pages
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
eBook
USD   169.00
Price excludes VAT (USA)
  • ISBN: 978-1-4939-9139-6
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
Hardcover Book
USD   219.99
Price excludes VAT (USA)
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Springer Nature is developing a new tool to find and evaluate Protocols. Learn more

References

  1. Lin D, Fantz CR, Levy B, Rafi MA, Vogler C, Wenger DA, Sands MS (2005) AAV2/5 vector expressing galactocerebrosidase ameliorates CNS disease in the murine model of globoid-cell leukodystrophy more efficiently than AAV2. Mol Ther 12(3):422–430. https://doi.org/10.1016/j.ymthe.2005.04.019

    CAS  CrossRef  PubMed  Google Scholar 

  2. McCurdy VJ, Johnson AK, Gray-Edwards HL, Randle AN, Brunson BL, Morrison NE, Salibi N, Johnson JA, Hwang M, Beyers RJ, Leroy SG, Maitland S, Denney TS, Cox NR, Baker HJ, Sena-Esteves M, Martin DR (2014) Sustained normalization of neurological disease after intracranial gene therapy in a feline model. Sci Transl Med 6(231):231ra248. https://doi.org/10.1126/scitranslmed.3007733

    CrossRef  Google Scholar 

  3. Carty NC, Nash K, Lee D, Mercer M, Gottschall PE, Meyers C, Muzyczka N, Gordon MN, Morgan D (2008) Adeno-associated viral (AAV) serotype 5 vector mediated gene delivery of endothelin-converting enzyme reduces abeta deposits in APP + PS1 transgenic mice. Mol Ther 16(9):1580–1586. https://doi.org/10.1038/mt.2008.148

    CAS  CrossRef  PubMed  Google Scholar 

  4. Connor B, Sun Y, von Hieber D, Tang SK, Jones KS, Maucksch C (2016) AAV1/2-mediated BDNF gene therapy in a transgenic rat model of Huntington’s disease. Gene Ther 23(3):283–295. https://doi.org/10.1038/gt.2015.113

    CAS  CrossRef  PubMed  Google Scholar 

  5. Oh SM, Chang MY, Song JJ, Rhee YH, Joe EH, Lee HS, Yi SH, Lee SH (2015) Combined Nurr1 and Foxa2 roles in the therapy of Parkinson’s disease. EMBO Mol Med 7(5):510–525. https://doi.org/10.15252/emmm.201404610

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  6. Foust KD, Salazar DL, Likhite S, Ferraiuolo L, Ditsworth D, Ilieva H, Meyer K, Schmelzer L, Braun L, Cleveland DW, Kaspar BK (2013) Therapeutic AAV9-mediated suppression of mutant SOD1 slows disease progression and extends survival in models of inherited ALS. Mol Ther 21(12):2148–2159. https://doi.org/10.1038/mt.2013.211

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  7. Stoica L, Todeasa SH, Cabrera GT, Salameh JS, ElMallah MK, Mueller C, Brown RH Jr, Sena-Esteves M (2016) Adeno-associated virus-delivered artificial microRNA extends survival and delays paralysis in an amyotrophic lateral sclerosis mouse model. Ann Neurol 79(4):687–700. https://doi.org/10.1002/ana.24618

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  8. Borel F, Gernoux G, Cardozo B, Metterville JP, Toro Cabrera GC, Song L, Su Q, Gao GP, Elmallah MK, Brown RH Jr, Mueller C (2016) Therapeutic rAAVrh10 mediated SOD1 silencing in adult SOD1(G93A) mice and nonhuman primates. Hum Gene Ther 27(1):19–31. https://doi.org/10.1089/hum.2015.122

    CAS  CrossRef  PubMed  Google Scholar 

  9. Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, Prior TW, Lowes L, Alfano L, Berry K, Church K, Kissel JT, Nagendran S, L’Italien J, Sproule DM, Wells C, Cardenas JA, Heitzer MD, Kaspar A, Corcoran S, Braun L, Likhite S, Miranda C, Meyer K, Foust KD, Burghes AHM, Kaspar BK (2017) Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med 377(18):1713–1722. https://doi.org/10.1056/NEJMoa1706198

    CAS  CrossRef  PubMed  Google Scholar 

  10. Foust KD, Poirier A, Pacak CA, Mandel RJ, Flotte TR (2008) Neonatal intraperitoneal or intravenous injections of recombinant adeno-associated virus type 8 transduce dorsal root ganglia and lower motor neurons. Hum Gene Ther 19(1):61–70. https://doi.org/10.1089/hum.2007.093

    CAS  CrossRef  PubMed  Google Scholar 

  11. Foust KD, Nurre E, Montgomery CL, Hernandez A, Chan CM, Kaspar BK (2009) Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat Biotechnol 27(1):59–65. https://doi.org/10.1038/nbt.1515

    CAS  CrossRef  PubMed  Google Scholar 

  12. Hinderer C, Katz N, Buza EL, Dyer C, Goode T, Bell P, Richman LK, Wilson JM (2018) Severe toxicity in nonhuman primates and piglets following high-dose intravenous administration of an adeno-associated virus vector expressing human SMN. Hum Gene Ther 29(3):285–298. https://doi.org/10.1089/hum.2018.015

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  13. Miyanohara A, Kamizato K, Juhas S, Juhasova J, Navarro M, Marsala S, Lukacova N, Hruska-Plochan M, Curtis E, Gabel B, Ciacci J, Ahrens ET, Kaspar BK, Cleveland D, Marsala M (2016) Potent spinal parenchymal AAV9-mediated gene delivery by subpial injection in adult rats and pigs. Mol Ther Methods Clin Dev 3:16046. https://doi.org/10.1038/mtm.2016.46

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  14. Tadokoro T, Miyanohara A, Navarro M, Kamizato K, Juhas S, Juhasova J, Marsala S, Platoshyn O, Curtis E, Gabel B, Ciacci J, Lukacova N, Bimbova K, Marsala M (2017) Subpial adeno-associated virus 9 (AAV9) vector delivery in adult mice. J Vis Exp (125). https://doi.org/10.3791/55770

  15. Usvald D, Vodicka P, Hlucilova J, Prochazka R, Motlik J, Kuchorova K, Johe K, Marsala S, Scadeng M, Kakinohana O, Navarro R, Santa M, Hefferan MP, Yaksh TL, Marsala M (2010) Analysis of dosing regimen and reproducibility of intraspinal grafting of human spinal stem cells in immunosuppressed minipigs. Cell Transplant 19(9):1103–1122. https://doi.org/10.3727/096368910X503406

    CrossRef  PubMed  Google Scholar 

  16. Naso MF, Tomkowicz B, Perry WL 3rd, Strohl WR (2017) Adeno-associated virus (AAV) as a vector for gene therapy. BioDrugs 31(4):317–334. https://doi.org/10.1007/s40259-017-0234-5

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  17. 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):2224–2232

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Carvalho LS, Xiao R, Wassmer SJ, Langsdorf A, Zinn E, Pacouret S, Shah S, Comander JI, Kim LA, Lim L, Vandenberghe LH (2018) Synthetic adeno-associated viral vector efficiently targets mouse and nonhuman primate retina in vivo. Hum Gene Ther 29(7):771–784. https://doi.org/10.1089/hum.2017.154

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Martin Marsala .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and Permissions

Copyright information

© 2019 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Verify currency and authenticity via CrossMark

Cite this protocol

Bravo-Hernández, M., Tadokoro, T., Marsala, M. (2019). Subpial AAV Delivery for Spinal Parenchymal Gene Regulation in Adult Mammals. In: Castle, M. (eds) Adeno-Associated Virus Vectors. Methods in Molecular Biology, vol 1950. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-9139-6_12

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-9139-6_12

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-9138-9

  • Online ISBN: 978-1-4939-9139-6

  • eBook Packages: Springer Protocols