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.

  • Original Article
  • Published:

Significantly increased lifespan and improved behavioral performances by rAAV gene delivery in adult mucopolysaccharidosis IIIB mice

Gene Therapy volume 14, pages 1065–1077 (2007)Cite this article

Abstract

Mucopolysaccharidosis (MPS) IIIB is an inherited lysosomal storage disease, caused by the deficiency of α-N-acetylglucosaminidase (NaGlu), resulting in severe global neurological involvement with high mortality. One major hurdle in therapeutic development for MPS IIIB is the presence of the blood–brain barrier, which impedes the global central nervous system (CNS) delivery of therapeutic materials. In this study, we used a minimal invasive strategy, combining an intravenous (i.v.) and an intracisternal (i.c.) injection, following an i.v. infusion of mannitol, to complement the CNS delivery of adeno-associated viral (AAV) vector for treating MPS IIIB in young adult mice. This treatment resulted in a significantly prolonged lifespan of MPS IIIB mice (11.1–19.5 months), compared with that without treatment (7.9–11.3), and correlated with significantly improved behavioral performances, the restoration of functional NaGlu, and variable correction of lysosomal storage pathology in the CNS, as well as in different somatic tissues. This study demonstrated the great potential of combining i.v. and i.c. administration for improving rAAV CNS gene delivery and developing rAAV gene therapy for treating MPS IIIB in patients.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  1. Neufeld EF, Muenzer J . The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds). The Metabolic & Molecular Basis of Inherited Disease. McGraw-Hill: New York, St Louis, San Francisco, 2001, pp 3421–3452.

    Google Scholar 

  2. Li HH, Yu WH, Rozengurt N, Zhao HZ, Lyons KM, Anagnostaras S et al. Mouse model of Sanfilippo syndrome type B produced by targeted disruption of the gene encoding alpha-N-acetylglucosaminidase. Proc Natl Acad Sci USA 1999; 96: 14505–14510.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. McGlynn R, Dobrenis K, Walkley SU . Differential subcellular localization of cholesterol, gangliosides, and glycosaminoglycans in murine models of mucopolysaccharide storage disorders. J Comp Neurol 2004; 480: 415–426.

    Article  CAS  PubMed  Google Scholar 

  4. Vellodi A, Young EP, Cooper A, Wraith JE, Winchester B, Meaney C et al. Bone marrow transplantation for mucopolysaccharidosis type I: experience of two British centres. Arch Dis Child 1997; 76: 92–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cox-Brinkman J, Boelens JJ, Wraith JE, O'Meara A, Veys P, Wijburg FA et al. Haematopoietic cell transplantation (HCT) in combination with enzyme replacement therapy (ERT) in patients with Hurler syndrome. Bone Marrow Transplant 2006; 38: 17–21.

    Article  CAS  PubMed  Google Scholar 

  6. Kakkis ED . Enzyme replacement therapy for the mucopolysaccharide storage disorders. Expert Opin Investig Drugs 2002; 11: 675–685.

    Article  CAS  PubMed  Google Scholar 

  7. Muenzer J, Lamsa JC, Garcia A, Dacosta J, Garcia J, Treco DA . Enzyme replacement therapy in mucopolysaccharidosis type II (Hunter syndrome): a preliminary report. Acta Paediatr Suppl 2002; 91: 98–99.

    Article  CAS  PubMed  Google Scholar 

  8. Weber B, Guo XH, Kleijer WJ, van de Kamp JJ, Poorthuis BJ, Hopwood JJ . Sanfilippo type B syndrome (mucopolysaccharidosis III B): allelic heterogeneity corresponds to the wide spectrum of clinical phenotypes. Eur J Hum Genet 1999; 7: 34–44.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  10. Leinekugel P, Michel S, Conzelmann E, Sandhoff K . Quantitative correlation between the residual activity of beta-hexosaminidase A and arylsulfatase A and the severity of the resulting lysosomal storage disease. Hum Genet 1992; 88: 513–523.

    Article  CAS  PubMed  Google Scholar 

  11. Abkowitz JL, Persik MT, Catlin SN, Guttorp P . Simulation of hematopoiesis: implications for the gene therapy of lysosomal enzyme disorders. Acta Haematol 1996; 95: 213–217.

    Article  CAS  PubMed  Google Scholar 

  12. Berns KI, Linden RM . The cryptic life style of adeno-associated virus. Bioessays 1995; 17: 237–245.

    Article  CAS  PubMed  Google Scholar 

  13. Fu H, Muenzer J, Samulski RJ, Breese G, Sifford J, Zeng X et al. Self-complementary adeno-associated virus serotype 2 vector: global distribution and broad dispersion of AAV-mediated transgene expression in mouse brain. Mol Ther 2003; 8: 911–917.

    Article  CAS  PubMed  Google Scholar 

  14. Kaplitt MG, Leone P, Samulski RJ, Xiao X, Pfaff DW, O'Malley KL 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 

  15. Elliger SS, Elliger CA, Aguilar CP, Raju NR, Watson GL . 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 

  16. Bosch A, Perret E, Desmaris N, Heard JM . Long-term and significant correction of brain lesions in adult mucopolysaccharidosis type VII mice using recombinant AAV vectors. Mol Ther 2000; 1: 63–70.

    Article  CAS  PubMed  Google Scholar 

  17. Fu HF, Samulski RJF, McCown TJF, Picornell YJF, Fletcher DF, Muenzer J . Neurological correction of lysosomal storage in a mucopolysaccharidosis IIIB mouse model by adeno-associated virus-mediated gene delivery. Mol Ther 2002; 5: 42–49.

    Article  CAS  PubMed  Google Scholar 

  18. Heuer GG, Passini MA, Jiang K, Parente MK, Lee VM, Trojanowski JQ et al. Selective neurodegeneration in murine mucopolysaccharidosis VII is progressive and reversible. Ann Neurol 2002; 52: 762–770.

    Article  PubMed  Google Scholar 

  19. Desmaris N, Verot L, Puech JP, Caillaud C, Vanier MT, Heard JM . Prevention of neuropathology in the mouse model of Hurler syndrome. Ann Neurol 2004; 56: 68–76.

    Article  CAS  PubMed  Google Scholar 

  20. Pardridge WM . Drug and gene delivery to the brain: the vascular route. Neuron 2002; 36: 555–558.

    Article  CAS  PubMed  Google Scholar 

  21. 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 

  22. Kaspar BK, Erickson D, Schaffer D, Hinh L, Gage FH, Peterson DA . Targeted retrograde gene delivery for neuronal protection. Mol Ther 2002; 5: 50–56.

    Article  CAS  PubMed  Google Scholar 

  23. Passini MA, Macauley SL, Huff MR, Taksir TV, Bu J, Wu IH et al. AAV vector-mediated correction of brain pathology in a mouse model of Niemann-Pick A disease. Mol Ther 2005; 11: 754–762.

    Article  CAS  PubMed  Google Scholar 

  24. Cressant A, Desmaris N, Verot L, Brejot T, Froissart R, Vanier MT et al. Improved behavior and neuropathology in the mouse model of Sanfilippo type IIIB disease after adeno-associated virus-mediated gene transfer in the striatum. J Neurosci 2004; 24: 10229–10239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sands MS, Barker JE . Percutaneous intravenous injection in neonatal mice. Lab Anim Sci 1999; 49: 328–330.

    CAS  PubMed  Google Scholar 

  26. Hartung SD, Frandsen JL, Pan D, Koniar BL, Graupman P, Gunther R et al. Correction of metabolic, craniofacial, and neurologic abnormalities in MPS I mice treated at birth with adeno-associated virus vector transducing the human alpha-L-iduronidase gene. Mol Ther 2004; 9: 866–875.

    Article  CAS  PubMed  Google Scholar 

  27. Kobayashi H, Carbonaro D, Pepper K, Petersen D, Ge S, Jackson H et al. Neonatal gene therapy of MPS I mice by intravenous injection of a lentiviral vector. Mol Ther 2005; 11: 776–789.

    Article  CAS  PubMed  Google Scholar 

  28. Mango RL, Xu L, Sands MS, Vogler C, Seiler G, Schwarz T et al. Neonatal retroviral vector-mediated hepatic gene therapy reduces bone, joint, and cartilage disease in mucopolysaccharidosis VII mice and dogs. Mol Genet Metab 2004; 82: 4–19.

    Article  CAS  PubMed  Google Scholar 

  29. Rapoport SI . Osmotic opening of the blood–brain barrier: principles, mechanism, and therapeutic applications. Cell Mol Neurobiol 2000; 20: 217–230.

    Article  CAS  PubMed  Google Scholar 

  30. Hall WA, Doolittle ND, Daman M, Bruns PK, Muldoon L, Fortin D et al. Osmotic blood–brain barrier disruption chemotherapy for diffuse pontine gliomas. J Neurooncol 2006; 77: 279–284.

    Article  CAS  PubMed  Google Scholar 

  31. Neuwelt EAF, Goldman DLF, Dahlborg SAF, Crossen JF, Ramsey FF, Roman-Goldstein SF et al. Primary CNS lymphoma treated with osmotic blood-brain barrier disruption: prolonged survival and preservation of cognitive function. J Clin Oncol 1991; 9: 1580–1590.

    Article  CAS  PubMed  Google Scholar 

  32. Wilson AJF, Evill CAF, Sage MR . Effects of nonionic contrast media on the blood–brain barrier. Osmolality versus chemotoxicity. Invest Radiol 1991; 26: 1091–1094.

    Article  CAS  PubMed  Google Scholar 

  33. Daly TM, Ohlemiller KK, Roberts MS, Vogler CA, Sands MS . Prevention of systemic clinical disease in MPS VII mice following AAV-mediated neonatal gene transfer. Gene Therapy 2001; 8: 1291–1298.

    Article  CAS  PubMed  Google Scholar 

  34. Daly TM, Vogler C, Levy B, Haskins ME, Sands MS . 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 

  35. Karolewski BA, Wolfe JH . Genetic correction of the fetal brain increases the lifespan of mice with the severe multisystemic disease mucopolysaccharidosis type VII. Mol Ther 2006; 14: 14–24.

    Article  CAS  PubMed  Google Scholar 

  36. Lin D, Fantz CR, Levy B, Rafi MA, Vogler C, Wenger DA et al. AAV2/5 vector expressing galactocerebrosidase ameliorates CNS disease in the murine model of globoid-cell leukodystrophy more efficiently than AAV2. Mol Ther 2005; 12: 422–430.

    Article  CAS  PubMed  Google Scholar 

  37. Cachon-Gonzalez MB, Wang SZ, Lynch A, Ziegler R, Cheng SH, Cox TM . Effective gene therapy in an authentic model of Tay-Sachs-related diseases. Proc Natl Acad Sci USA 2006; 103: 10373–10378.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kakkis ED, Muenzer J, Tiller GE, Waber L, Belmont J, Passage M et al. Enzyme-replacement therapy in mucopolysaccharidosis I. N Engl J Med 2001; 344: 182–188.

    Article  CAS  PubMed  Google Scholar 

  39. Crawley AC, King B, Berg T, Meikle PJ, Hopwood JJ . Enzyme replacement therapy in alpha-mannosidosis guinea-pigs. Mol Genet Metab 2006; 89: 48–57.

    Article  CAS  PubMed  Google Scholar 

  40. Harmatz P, Ketteridge D, Giugliani R, Guffon N, Teles EL, Miranda MC et al. Direct comparison of measures of endurance, mobility, and joint function during enzyme-replacement therapy of mucopolysaccharidosis VI (Maroteaux–Lamy syndrome): results after 48 weeks in a phase 2 open-label clinical study of recombinant human N-acetylgalactosamine 4-sulfatase. Pediatrics 2005; 115: e681–e689.

    Article  PubMed  Google Scholar 

  41. Zhao KW, Neufeld EF . Purification and characterization of recombinant human alpha-N-acetylglucosaminidase secreted by Chinese hamster ovary cells. Protein Expr Purif 2000; 19: 202–211.

    Article  CAS  PubMed  Google Scholar 

  42. Weber B, Hopwood JJ, Yogalingam G . Expression and characterization of human recombinant and alpha-N-acetylglucosaminidase. Protein Expr Purif 2001; 21: 251–259.

    Article  CAS  PubMed  Google Scholar 

  43. Ni X, Morales CR . The lysosomal trafficking of acid sphingomyelinase is mediated by sortilin and mannose 6-phosphate receptor. Traffic 2006; 7: 889–902.

    Article  CAS  PubMed  Google Scholar 

  44. Gliddon BL, Hopwood JJ . Enzyme-replacement therapy from birth delays the development of behavior and learning problems in mucopolysaccharidosis type IIIA mice. Pediatr Res 2004; 56: 65–72.

    Article  CAS  PubMed  Google Scholar 

  45. Harmatz P, Whitley CB, Waber L, Pais R, Steiner R, Plecko B et al. Enzyme replacement therapy in mucopolysaccharidosis VI (Maroteaux–Lamy syndrome). J Pediatr 2004; 144: 574–580.

    Article  CAS  PubMed  Google Scholar 

  46. Vogler C, Sands MS, Levy B, Galvin N, Birkenmeier EH, Sly WS . Enzyme replacement with recombinant beta-glucuronidase in murine mucopolysaccharidosis type VII: impact of therapy during the first six weeks of life on subsequent lysosomal storage, growth, and survival. Pediatr Res 1996; 39: 1050–1054.

    Article  CAS  PubMed  Google Scholar 

  47. Zhao HG, Li HH, Bach G, Schmidtchen A, Neufeld EF . The molecular basis of Sanfilippo syndrome type B. Proc Natl Acad Sci USA 1996; 93: 6101–6105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zolotukhin S, Byrne BJ, Mason E, Zolotukhin I, Potter M, Chesnut K et al. Recombinant adeno-associated virus purification using novel methods improves infectious titer and yield. Gene Therapy 1999; 6: 973–985.

    Article  CAS  PubMed  Google Scholar 

  49. Thompson JN, Nowakoski RW . Enzymatic diagnosis of selected mucopolysaccharidoses: Hunter, Morquio type A, and Sanfilippo types A, B, C, and D, and procedures for measurement of 35SO4-glycosaminoglycans. In: Hommes FA (ed). Techniques in Diagnostic Human Biochemical Genetics – A Laboratory Manual. Wiley-Liss: New York, 1991, pp 567–586.

    Google Scholar 

  50. van de Lest CH, Versteeg EM, Veerkamp JH, van Kuppevelt TH . Quantification and characterization of glycosaminoglycans at the nanogram level by a combined azure A-silver staining in agarose gels. Anal Biochem 1994; 221: 356–361.

    Article  CAS  PubMed  Google Scholar 

  51. de Jong JG, Wevers RA, Laarakkers C, Poorthuis BJ . Dimethylmethylene blue-based spectrophotometry of glycosaminoglycans in untreated urine: a rapid screening procedure for mucopolysaccharidoses. Clin Chem 1989; 35: 1472–1477.

    CAS  PubMed  Google Scholar 

  52. Lijam N, Paylor R, McDonald MP, Crawley JN, Deng CX, Herrup K et al. Social interaction and sensorimotor gating abnormalities in mice lacking Dvl1. Cell 1997; 90: 895–905.

    Article  CAS  PubMed  Google Scholar 

  53. Warburton EC, Baird A, Morgan A, Muir JL, Aggleton JP . The conjoint importance of the hippocampus and anterior thalamic nuclei for allocentric spatial learning: evidence from a disconnection study in the rat. J Neurosci 2001; 21: 7323–7330.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Most of the experiments in this study were conducted in the laboratory of Dr Joseph Muenzer, Department of Pediatrics. UNC-CH, Haiyan Fu and Lu Kang made equal contribution. We thank Dr Elizabeth F Neufeld for generously providing us the hNaGlu antibody. This study was sponsored by NIDDK (R01 DK63972) and Ben's Dream-Sanfilippo Research Foundation.

Author information

Authors and Affiliations

  1. Center for Gene Therapy, Columbus Children's Research Institute, Columbus, OH, USA

    H Fu, J DiRosario & D M McCarty

  2. Department of Pediatrics, Ohio State University, Columbus, OH, USA

    H Fu & D M McCarty

  3. Department of Pediatrics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    L Kang, J S Jennings & J Muenzer

  4. Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    S S Moy

  5. Neurodevelopmental Disorders Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    S S Moy & A Perez

Authors
  1. H Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J S Jennings
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S S Moy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Perez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J DiRosario
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D M McCarty
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J Muenzer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H Fu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fu, H., Kang, L., Jennings, J. et al. Significantly increased lifespan and improved behavioral performances by rAAV gene delivery in adult mucopolysaccharidosis IIIB mice. Gene Ther 14, 1065–1077 (2007). https://doi.org/10.1038/sj.gt.3302961

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302961

Keywords

This article is cited by

Search

Advanced search

Quick links