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Transduction patterns in the CNS following various routes of AAV-5-mediated gene delivery

Abstract

Various administration routes of adeno-associated virus (AAV)-based gene therapy have been examined to target the central nervous system to answer the question what the most optimal delivery route is for treatment of the brain with certain indications. In this study, we evaluated AAV5 vector system for its capability to target the central nervous system via intrastriatal, intrathalamic or intracerebroventricular delivery routes in rats. AAV5 is an ideal candidate for gene therapy because of its relatively low level of existing neutralizing antibodies compared to other serotypes, and its broad tissue and cell tropism. Intrastriatal administration of AAV5-GFP resulted in centralized localized vector distribution and expression in the frontal part of the brain. Intrathalamic injection showed transduction and gradient expression from the rostral brain into lumbar spinal cord, while intracerebroventricular administration led to a more evenly, albeit relatively superficially distributed, transduction and expression throughout the central nervous system. To visualize the differences between localized and intra-cerebral spinal fluid administration routes, we compared intrastriatal to intracerebroventricular and intrathecal administration of AAV5-GFP. Together, our results demonstrate that for efficient transgene expression, various administration routes can be applied.

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Fig. 1: Overview of injection routes.
Fig. 2: Vector distribution and GFP expression following various cerebral administration routes of AAV5-GFP in rats.
Fig. 3: GFP expression throughout the rat brain following intrastriatal (IStr), intracerebroventricular (ICV), or intrathecal (IT) administration of AAV5-GFP.
Fig. 4: GFP expression in cortex and striatum in rat brain following intrastriatal (IStr), intracerebroventricular (ICV), or intrathecal (IT) administration of AAV5-GFP.
Fig. 5: GFP expression in the hippocampal area in rat brain intrastriatal (IStr), intracerebroventricular (ICV), or intrathecal (IT) administration of AAV5-GFP.
Fig. 6: GFP staining in the midbrain area and cerebellum in rat brain following intrastriatal (IS), intracerebroventricular (ICV), or intrathecal (IT) administration of AAV5-GFP.
Fig. 7: GFP staining in the spinal cord and the dorsal root ganglion of intracerebroventricular (ICV) and intrathecal (IT) administered AAV5 rats.

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References

  1. Leone P, Shera D, McPhee S, Francis JS, Kolodny EH, Bilaniuk LT, et al. Long-term follow-up after gene therapy for canavan disease. Sci Transl Med. 2012;4:165ra163–165ra163.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Boutin S, Monteilhet V, Veron P, Leborgne C, Benveniste O, Montus M, et al. 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. 2010;21:704–12.

    Article  CAS  PubMed  Google Scholar 

  3. Aschauer DF, Kreuz S, Rumpel S. Analysis of transduction efficiency, tropism and axonal transport of AAV serotypes 1, 2, 5, 6, 8 and 9 in the mouse brain. PloS ONE. 2013;8:e76310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Lisowski L, Tay S, Alexander I. Adeno-associated virus serotypes for gene therapeutics. Curr Opin Pharmacol. 2015;24:59–67.

    Article  CAS  PubMed  Google Scholar 

  5. Paterna J-C, Feldon J, Büeler H. Transduction profiles of recombinant adeno-associated virus vectors derived from serotypes 2 and 5 in the nigrostriatal system of rats. J Virol. 2004;78:6808–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Dodiya HB, Bjorklund T III, J Mandel RJ, Kirik D, Kordower JH. Differential transduction following basal ganglia administration of distinct pseudotyped AAV capsid serotypes in nonhuman primates. Mol Ther. 2010;18:579–87.

    Article  CAS  PubMed  Google Scholar 

  7. Markakis EA, Vives KP, Bober J, Leichtle S, Leranth C, Beecham J, et al. Comparative transduction efficiency of AAV vector serotypes 1–6 in the substantia nigra and striatum of the primate brain. Mol Ther. 2010;18:588–93.

    Article  CAS  PubMed  Google Scholar 

  8. Samaranch L, Blits B, Sebastian SW, Hadaczek P, Bringas J, Sudhakar V, et al. MR-guided parenchymal delivery of adeno-associated viral vector serotype 5 in non-human primate brain. Gene Ther. 2017;24:253–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Martier R, Liefhebber JM, García-Osta A, Miniarikova J, Cuadrado-Tejedor M, Espelosin M, et al. Targeting RNA-mediated toxicity in C9ORF72 ALS/FTD by RNAi-based gene therapy. Mol Ther—Nucleic Acids. 2019;16:26–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Schuster DJ, Belur LR, Riedl MS, Schnell SA, Podetz-Pedersen KM, Kitto KF, et al. Supraspinal gene transfer by intrathecal adeno-associated virus serotype 5. Front Neuroanat. 2014;8:66.

    PubMed  PubMed Central  Google Scholar 

  11. Schapira A, Chiasserini D, Beccari T, Parnetti L. Glucocerebrosidase in Parkinson’s disease: insights into pathogenesis and prospects for treatment. Movement Disord. 2016;31:830–5.

    Article  PubMed  Google Scholar 

  12. Reiner A, Dragatsis I, Dietrich P.Genetics and neuropathology of Huntington's disease. Int Rev Neurobiol. 2011;98:325–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Salegio E, Samaranch L, Kells A, Mittermeyer G, Sebastian SW, Zhou S, et al. Axonal transport of adeno-associated viral vectors is serotype-dependent. Gene Ther. 2012;20:gt201227.

    Google Scholar 

  14. Furman JL, ma D, Gant JC, Beckett TL, Murphy PM, Bachstetter AD, et al. Targeting astrocytes ameliorates neurologic changes in a mouse model of Alzheimer’s disease. J Neurosci. 2012;32:16129–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hardcastle N, Boulis NM, Federici T. AAV gene delivery to the spinal cord: serotypes, methods, candidate diseases, and clinical trials. Exp Opin Biol Ther. 2017;18:1–15.

    Google Scholar 

  16. Tardieu M, Zérah M, Gougeon M-L, Ausseil J, de Bournonville S, Husson B, et al. Intracerebral gene therapy in children with mucopolysaccharidosis type IIIB syndrome: an uncontrolled phase 1/2 clinical trial. Lancet Neurol. 2017. https://doi.org/10.1016/s1474-4422(17)30169-2.

    Article  PubMed  Google Scholar 

  17. Bosma B, du Plessis F, Ehlert E, Nijmeijer B, de Haan M, Petry H, et al. Optimization of viral protein ratios for production of rAAV serotype 5 in the baculovirus system. Gene Ther. 2018;25:415–24.

    Article  CAS  PubMed  Google Scholar 

  18. Oudega M, Varon S, Hagg T. Regeneration of adult rat sensory axons into intraspinal nerve grafts: promoting effects of conditioning lesion and graft predegeneration. Exp Neurol. 1994;129:194–206.

    Article  CAS  PubMed  Google Scholar 

  19. Gray SJ, Foti SB, Schwartz JW, Bachaboina L, Taylor-Blake B, Coleman J, et al. Optimizing promoters for recombinant adeno-associated virus-mediated gene expression in the peripheral and central nervous system using self-complementary vectors. Hum Gene Ther. 2011;22:1143–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Casaca-Carreira J, Temel Y, Hescham S-A, Jahanshahi A. Transependymal cerebrospinal fluid flow: opportunity for drug delivery? Mol Neurobiol. 2018;55:2780–8.

    Article  CAS  PubMed  Google Scholar 

  21. Schuster DJ, Dykstra JA, Riedl MS, Kitto KF, Belur LR, McIvor SR, et al. Biodistribution of adeno-associated virus serotype 9 (AAV9) vector after intrathecal and intravenous delivery in mouse. Front Neuroanat. 2014;8:42.

    PubMed  PubMed Central  Google Scholar 

  22. Guo Y, Wang D, Qiao T, Yang C, Su Q, Gao G, et al. A single injection of recombinant adeno-associated virus into the lumbar cistern delivers transgene expression throughout the whole spinal cord. Mol Neurobiol. 2016;53:3235–48.

    Article  CAS  PubMed  Google Scholar 

  23. Meyer K, Ferraiuolo L, Schmelzer L, Braun L, McGovern V, Likhite S, et al. Improving single injection CSF delivery of AAV9-mediated gene therapy for SMA: a dose–response study in mice and nonhuman primates. Mol Ther. 2015;23:477–87.

    Article  CAS  PubMed  Google Scholar 

  24. Chen B, He C, Chen X, Pan S, Liu F, Ma X, et al. Targeting transgene to the heart and liver with AAV9 by different promoters. Clin Exp Pharmacol Physiol. 2015;42:1108–17.

    Article  CAS  PubMed  Google Scholar 

  25. Cearley CN, Wolfe JH. Transduction characteristics of adeno-associated virus vectors expressing cap serotypes 7, 8, 9, and Rh10 in the mouse brain. Mol Ther. 2006;13:528–37.

    Article  CAS  PubMed  Google Scholar 

  26. Emborg ME, Hurley SA, Joers V, Tromp DPM, Swanson CR, Ohshima-Hosoyama S, et al. Titer and product affect the distribution of gene expression after intraputaminal convection-enhanced delivery. Stereotactic Funct Neurosurg. 2014;92:182–94.

    Article  Google Scholar 

  27. Haurigot V, Marcó S, Ribera A, Garcia M, Ruzo A, Villacampa P, et al. Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy. J Clin Investig. 2013;123:3254–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Evers MM, Miniarikova J, Juhas S, Vallès A, Bohuslavova B, Juhasova J. et al. AAV5-miHTT gene therapy demonstrates broad distribution and strong human mutant huntingtin lowering in a Huntington disease minipig model. Mol Ther. 2018;26:2163–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like thank E. Broug and E. Sawyer for critically reviewing this manuscript.

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Pietersz, K.L., Martier, R.M., Baatje, M.S. et al. Transduction patterns in the CNS following various routes of AAV-5-mediated gene delivery. Gene Ther 28, 435–446 (2021). https://doi.org/10.1038/s41434-020-0178-0

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