Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Research Article
  • Published:

Adeno-associated virus vector-mediated transduction in the cat brain

Abstract

Adeno-associated virus (AAV) vectors are capable of delivering a therapeutic gene to the mouse brain that can result in long-term and widespread protein production. However, the human infant brain is more than 1000 times larger than the mouse brain, which will make the treatment of global neurometabolic disorders in children more difficult. In this study, we evaluated the ability of three AAV serotypes (1,2, and 5) to transduce cells in the cat brain as a model of a large mammalian brain. The human lysosomal enzyme β-glucuronidase (GUSB) was used as a reporter gene, because it can be distinguished from feline GUSB by heat stability. The vectors were injected into the cerebral cortex, caudate nucleus, thalamus, corona radiata, internal capsule, and centrum semiovale of 8-week-old cats. The brains were evaluated for gene expression using in situ hybridization and enzyme histochemistry 10 weeks after surgery. The AAV2 vector was capable of transducing cells in the gray matter, while the AAV1 vector resulted in greater transduction of the gray matter than AAV2 as well as transduction of the white matter. AAV5 did not result in detectable transduction in the cat brain.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Scriver CR, Beaudet AL, Sly WS, Valle D . Metabolic Bases of Inherited Disease 8th edn. McGraw Hill: NY, 2001, pp 3369–3894.

    Google Scholar 

  2. Sly WS, Vogler C . Brain-directed gene therapy for lysosomal storage disease: going well-beyond the blood–brain barrier. Proc Natl Acad Sci USA 2002; 99: 5760–5762.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Skorupa AF et al. Sustained production of β-glucuronidase from localized sites after AAV vector gene transfer results in widespread distribution of enzyme and reversal of lysosomal storage lesions in a large volume of brain in muco-polysaccharidosis VII mice. Exp Neurol 1999; 160: 17–27.

    Article  CAS  PubMed  Google Scholar 

  4. Daly TM et al. Neonatal gene transfer leads to widespread correction of pathology in a murine model of lysosomal storage disease. Proc Natl Acad Sci USA 1999; 96: 2296–2300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Elliger SS et al. Elimination of lysosomal storage in brains of MPS VII mice treated by intrathecal administration of an adeno-associated virus vector. Gene Therapy 1999; 6: 1175–1178.

    Article  CAS  PubMed  Google Scholar 

  6. Ghodsi A et al. Systemic hyperosmolality improves β-glucuronidase distribution and pathology in murine MPS VII brain following intraventricular gene transfer. Exp Neurol 1999; 160: 109–116.

    Article  CAS  PubMed  Google Scholar 

  7. Bosch A et al. Reversal of pathology in the entire brain of mucopolysaccharidosis type VII mice after lentivirus-mediated gene transfer. Hum Gen Ther 2000; 11: 1139–1150.

    Article  CAS  Google Scholar 

  8. Passini MA, Wolfe JH . Widespread gene delivery and structure specific patterns of expression in the brain after intraventricular injections of neonatal mice with an adeno-associated virus vector. J Virol 2001; 75: 12382–12392.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Brooks AI 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 2002; 99: 6216–6221.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Summers BA, Cummings JF, de Lahunta A . Veterinary Neuropathology., Mosby: St Louis, MO, 1995.

    Google Scholar 

  11. Jolly RD, Walkley SU . Lysosomal storage diseases of animals: an essay in comparative pathology. Vet Pathol 1997; 34: 527–548.

    Article  CAS  PubMed  Google Scholar 

  12. Watson DJ, Wolfe JH . Lentiviral vectors for gene transfer to the central nervous system: applications in lysosomal storage disease animal models. In: Machida C (ed). Viral Vectors for Gene Therapy: Methods and Protocols, Humana Press: Totowa, NJ, 2002 pp 383–403.

    Chapter  Google Scholar 

  13. Berman AL . The Brain Stem Of The Cat, A Cytoarchitectonic Atlas With Stereotaxic Coordinates, University of Wisconsin Press: Madison, 1968.

    Google Scholar 

  14. Berman AL, Jones EG . The Thalamus And Basal Telencephalon of the Cat: A Cytoarchitectonic Atlas with Stereotaxic Coordinates, University of Wisconsin Press: Madison, 1982.

    Google Scholar 

  15. Rabinowitz JE, Samulski RJ . Building a better vector: the manipulation of AAV virions. Virology 2000; 278: 301–308.

    Article  CAS  PubMed  Google Scholar 

  16. Gao G-P et al. Novel adeno-associated viruses for rhesus monkeys as vectors for human gene delivery. Proc Natl Acad Sci USA 2002; 99: 11854–11859.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Davidson BL et al. Recombinant adeno-associated virus type 2, 4, and 5 vectors: transduction of variant cell types and regions of the mammalian central nervous system. Proc Natl Acad Sci USA 2000; 97: 3428–3432.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wolfe JH, Deshmane SL, Fraser NW . Herpesvirus vector gene transfer and expression of β-glucuronidase in the central nervous system of MPS VII mice. Nat Genet 1992; 1: 379–384.

    Article  CAS  PubMed  Google Scholar 

  19. Casal ML, Wolfe JH . In utero transplantation of fetal liver cells in the mucopolysaccharidosis type VII mouse results in low-level chimerism, but overexpression of beta-glucuronidase can delay onset of clinical signs. Blood 2001; 97: 1625–1634.

    Article  CAS  PubMed  Google Scholar 

  20. Fratantoni JC, Hall CW, Neufeld EF . Hurler and Hunter syndromes: mutual correction of the defect in cultures fibroblasts. Science 1968; 162: 570–572.

    Article  CAS  PubMed  Google Scholar 

  21. Taylor RM, Wolfe JH . Decreased lysosomal storage in the adult MPS VII mouse brain in the vicinity of grafts of retroviral vector-corrected fibroblasts secreting high levels of β-glucuronidase. Nat Med 1997; 3: 771–774.

    Article  CAS  PubMed  Google Scholar 

  22. Chirioni JA et al. Cloning of adeno-associated virus type 4 (AAV4) and generation of recombinant AAV4 particles. J Virol 1997; 71: 6823–6833.

    Google Scholar 

  23. Rutledge EA, Halbert CL, Russell DW . Infectious clones and vectors derived from adeno-associated virus (AAV) serotypes other than AAV type 2. J Virol 1998; 72: 309–319.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Bantel-Schaal U, Delius H, Schmidt R, zur Hausen H . Human adeno-associated virus type 5 is only distantly related to other known primate helper-dependent parvoviruses. J Virol 1999; 73: 939–947.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Chiorini JA, Kim F, Yang L, Kotin RM . Cloning and characterization of adeno-associated virus type 5. J Virol 1999; 73: 1309–1319.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Xiao W et al. Gene therapy based on adeno-associated virus type 1. J Virol 1999; 73: 3994–4003.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Summerford C, Samulski RJ . Membrane-associated heparan sulfate proteoglycan is a receptor for adeno-associated virus type-2 virions. J Virol 1998; 72: 1438–1445.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Duan D et al. Enhancement of muscle delivery with pseudotypes adeno-associated virus type 5 correlates with myoblast differentiation. J Virol 2001; 75: 7662–7671.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Rabinowitz JE et al. Cross-packaging of a single adeno-associated virus (AAV) type 2 vector genome into multiple AAV serotypes enables transduction with broad specificity. J Virol 2002; 76: 791–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Walters RW et al. Binding of adeno-associated virus type 5 to 2,3-linked sialic acid is required for gene transfer. J Biol Chem 2001; 276: 20610–20616.

    Article  CAS  PubMed  Google Scholar 

  31. Sferra TJ et al. Recombinant adeno-associated virus-mediated correction of lysosomal storage within the central nervous system of the adult mucopolysaccharidosis Type VII mouse. Hum Gene Ther 2000; 11: 507–519.

    Article  CAS  PubMed  Google Scholar 

  32. Elliger SS, Elliger CA, Lang C, Watson GL . Enhanced secretion and uptake of β-glucuronidase improves adeno-associated viral-mediated gene therapy of mucopolysaccharidosis Type VII mice. Mol Ther 2002; 5: 617–626.

    Article  CAS  PubMed  Google Scholar 

  33. Frisella WA et al. Intracranial injection of recombinant adeno-associated virus improves cognitive function in a murine model of mucopolysaccharidosis Type VII. Mol Ther 2001; 3: 351–358.

    Article  CAS  PubMed  Google Scholar 

  34. Fu H et al. Neurological correction of lysosomal storage in a mucopolysaccharidosis IIIB mouse model by adeno-associated virus-mediated gene therapy. Mol Ther 2002; 5: 42–49.

    Article  CAS  PubMed  Google Scholar 

  35. Alisky JM et al. Tranduction of murine cerebellar neurons with recombinant FIV and AAV5 vectors. Mol Neurosci 2000; 11: 2669–2673.

    CAS  Google Scholar 

  36. Kaplitt MG et al. Long-term gene expression and phenotypic correction using adeno-associated virus vectors in the mammalian brain. Nat Genet 1994; 8: 148–154.

    Article  CAS  PubMed  Google Scholar 

  37. McCown TJ et al. Differential and persistent expression of CNS gene transfer by an adeno-associated virus (AAV) vector. Brain Res 1996; 713: 99–107.

    Article  CAS  PubMed  Google Scholar 

  38. During MJ et al. In vivo expression of therapeutic genes for dopamine production in the caudates of MPTP-treated monkeys using an AAV vector. Gene Therapy 1998; 5: 820–827.

    Article  CAS  PubMed  Google Scholar 

  39. Peel AL, Klein RL . Adeno-associated virus vectors: activity and applications in the CNS. J Neurosci Methods 2000; 98: 95–104.

    Article  CAS  PubMed  Google Scholar 

  40. Shimazaki K et al. Adeno-associated virus vector-mediated bcl-2 gene transfer into post-ischemic gerbil brain in vivo: prospects for gene therapy of ischemic-induced neuronal death. Gene Therapy 2000; 7: 1244–1249.

    Article  CAS  PubMed  Google Scholar 

  41. Mastakov MY, Baer K, Kotin RM, During MJ . Recombinant adeno-associated virus serotypes 2-and 5-mediated gene transfer in the mammalian brain: quantitative analysis of heparin co-infusion. Mol Ther 2002; 5: 371–380.

    Article  CAS  PubMed  Google Scholar 

  42. Passini MA, Lee EB, Heuer GG, Wolfe JH . Distribution of a lysosomal enzyme in the adult brain by axonal transport and by cells of the rostral migratory stream. J Neurosci 2002; 22: 6436–6446.

    Article  Google Scholar 

  43. Bartlett JS, Samulski RJ, McCown TJ . Selective and rapid uptake of adeno-associated virus type 2 in brain. Hum Gene Ther 1998; 9: 1181–1186.

    Article  CAS  PubMed  Google Scholar 

  44. Hildinger M et al. Hybrid vectors based on adeno-associated virus serotypes 2 and 5 for muscle-directed gene transfer. J Virol 2001; 75: 6199–6203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Heuer GG et al. Selective neurodegeneration in murine mucopolysaccharidosis VII is progressive and reversible. Ann Neurol 2002; 52: 762–770.

    Article  PubMed  Google Scholar 

  46. Barthel LK, Raymond PA . In situ hybridization studies of retinal neurons. Methods Enzymol 2000; 316: 579–590.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

CHV was supported by a K08 from NINDS (NS02032) and MAP by an NIH training grant (DK07748). We thank P O'Donnell, J Zweigel, and T O'Malley and the Animal Models Core of the School of Veterinary Medicine (RR02512) for assistance with the animal procedures; AC Polesky and B Chambers for assistance in sectioning and processing tissue; M Parente for assistance in image analysis; and L Wang and the Vector Core of the University of Pennsylvania (DK47747) for assistance in viral vector production. This work was supported in part by NIH Grants NS38690, DK63973, and DK49652.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vite, C., Passini, M., Haskins, M. et al. Adeno-associated virus vector-mediated transduction in the cat brain. Gene Ther 10, 1874–1881 (2003). https://doi.org/10.1038/sj.gt.3302087

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302087

Keywords

This article is cited by

Search

Quick links