Skip to main content

Characterization of a novel mucopolysaccharidosis type II mouse model and recombinant AAV2/8 vector-mediated gene therapy

Molecules and Cells volume 30, pages 13–18 (2010)Cite this article

Abstract

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is an X-linked inherited disorder caused by a deficiency of the enzyme iduronate-2-sulfatase (IDS), which results in the lysosomal accumulation of glycosaminoglycans (GAG) such as dermatan and heparan sulfate. Here, we report the generation of IDS knockout mice, a model of human MPS II, and an analysis of the resulting phenotype. We also evaluated the effect of gene therapy with a pseudotyped, recombinant adeno-associated virus 2/8 vector encoding the human IDS gene (rAAV-hIDS) in IDS-deficient mice. IDS activity and GAG levels were measured in serum and tissues after therapy. Gene therapy completely restored IDS activity in plasma and tissue of the knockout mice. The rescued enzymatic activity completely cleared the accumulated GAGs in all the tissues analyzed. This model can be used to explore the therapeutic potential of IDS replacement and other strategies for the treatment of MPS II. Additionally, AAV2/8 vectors have promising future clinical applications for the treatment of patients with MPS II.

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

References

  • Birkenmeier, E.H., Davisson, M.T., Beamer, W.G., Ganschow, R.E., Vogler, C.A., Gwynn, B., Lyford, K.A., Maltais, L.M., and Wawrzyniak, C.J. (1989). Murine mucopolysaccharidosis type VII. Characterization of a mouse with beta-glucuronidase deficiency. J. Clin. Invest. 83, 1258–1266.

    Article  CAS  PubMed  Google Scholar 

  • Braun, S.E., Aronovich, E.L., Anderson, R.A., Crotty, P.L., McIvor, R.S., and Whitley, C.B. (1993). Metabolic correction and cross-correction of mucopolysaccharidosis type II (Hunter syndrome) by retroviral-mediated gene transfer and expression of human iduronate-2-sulfatase. Proc. Natl. Acad. Sci. USA 90, 11830–11834.

    Article  CAS  PubMed  Google Scholar 

  • Brooks, D.A., Kakavanos, R., and Hopwood, J.J. (2003). Significance of immune response to enzyme-replacement therapy for patients with a lysosomal storage disorder. Trends Mol. Med. 9, 450–453.

    Article  CAS  PubMed  Google Scholar 

  • Cardone, M., Polito, V.A., Pepe, S., Mann, L., D’Azzo, A., Auricchio, A., Ballabio, A., and Cosma, M.P. (2006). Correction of Hunter syndrome in the MPS II mouse model by AAV2/8-mediated gene delivery. Hum. Mol. Genet. 15, 1225–1236.

    Article  CAS  PubMed  Google Scholar 

  • Clarke, L.A., Russell, C.S., Pownall, S., Warrington, C.L., Borowski, A., Dimmick, J.E., Toone, J., and Jirik, F.R. (1997). Murine mucopolysaccharidosis type I: targeted disruption of the murine alpha-L-iduronidase gene. Hum. Mol. Genet. 6, 503–511.

    Article  CAS  PubMed  Google Scholar 

  • Coppa, G.V., Gabrielli, O., Zampini, L., Pierani, P., Giorgi, P.L., Jezequel, A.M., Orlandi, F., Miniero, R., Busca, A., De Luca, T., et al. (1995). Bone marrow transplantation in Hunter syndrome (mucopolysaccharidosis type II): two-year follow-up of the first Italian patient and review of the literature. Pediatr. Med. Chir. 17, 227–235.

    CAS  PubMed  Google Scholar 

  • Daniele, A., Tomanin, R., Villani, G.R., Zacchello, F., Scarpa, M., and Di Natale, P. (2002). Uptake of recombinant iduronate-2-sulfatase into neuronal and glial cells in vitro. Biochim. Biophys. Acta 1588, 203–209.

    CAS  PubMed  Google Scholar 

  • Daya, S., and Berns, K.I. (2008). Gene therapy using adeno-associated virus vectors. Clin. Microbiol. Rev. 21, 583–593.

    Article  CAS  PubMed  Google Scholar 

  • Di Francesco, C., Cracco, C., Tomanin, R., Picci, L., Ventura, L., Zacchello, E., Di Natale, P., Anson, D.S., Hopwood, J.J., Graham, F.L., et al. (1997). In vitro correction of iduronate-2-sulfatase deficiency by adenovirus-mediated gene transfer. Gene Ther. 4, 442–448.

    Article  PubMed  Google Scholar 

  • Evers, M., Saftig, P., Schmidt, P., Hafner, A., McLoghlin, D.B., Schmahl, W., Hess, B., von Figura, K., and Peters, C. (1996). Targeted disruption of the arylsulfatase B gene results in mice resembling the phenotype of mucopolysaccharidosis VI. Proc. Natl. Acad. Sci. USA 93, 8214–8219.

    Article  CAS  PubMed  Google Scholar 

  • Garcia, A.R., Pan, J., Lamsa, J.C., and Muenzer, J. (2007). The characterization of a murine model of mucopolysaccharidosis II (Hunter syndrome). J. Inherit. Metab. Dis. 30, 924–934.

    Article  CAS  PubMed  Google Scholar 

  • Grimm, D., Pandey, K., Nakai, H., Storm, T.A., and Kay, M.A. (2006). Liver transduction with recombinant adeno-associated virus is primarily restricted by capsid serotype not vector genotype. J. Virol. 80, 426–439.

    Article  CAS  PubMed  Google Scholar 

  • Hacein-Bey-Abina, S., von Kalle, C., Schmidt, M., Le Deist, F., Wulffraat, N., McIntyre, E., Radford, I., Villeval, J.L., Fraser, C.C., Cavazzana-Calvo, M., et al. (2003). A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N. Engl. J. Med. 348, 255–256.

    Article  PubMed  Google Scholar 

  • Jung, S.C., Han, I.P., Limaye, A., Xu, R., Gelderman, M.P., Zerfas, P., Tirumalai, K., Murray, G.J., During, M.J., Brady, R.O., et al. (2001). Adeno-associated viral vector-mediated gene transfer results in long-term enzymatic and functional correction in multiple organs of Fabry mice. Proc. Natl. Acad. Sci. USA 98, 2676–2681.

    Article  CAS  PubMed  Google Scholar 

  • Ko, J.Y., Ahn, Y.L., and Cho, B.N. (2003). Angiogenesis and white blood cell proliferation induced in mice by injection of a prolactin-expressing plasmid into muscle. Mol. Cells 15, 262–270.

    CAS  PubMed  Google Scholar 

  • Li, P., Thompson, J.N., Hug, G., Huffman, P., and Chuck, G. (1996). Biochemical and molecular analysis in a patient with the severe form of Hunter syndrome after bone marrow transplantation. Am. J. Med. Genet. 64, 531–535.

    Article  CAS  PubMed  Google Scholar 

  • Li, H.H., Yu, W.H., Rozengurt, N., Zhao, H.Z., Lyons, K.M., Anagnostaras, S., Fanselow, M.S., Suzuki, K., Vanier, M.T., and Neufeld, E.F. (1999). Mouse model of Sanfilippo syndrome type B produced by targeted disruption of the gene encoding alpha-N-acetylglucosaminidase. Proc. Natl. Acad. Sci. USA 96, 14505–14510.

    Article  CAS  PubMed  Google Scholar 

  • Liu, Q., and Muruve, D.A. (2003). Molecular basis of the inflammatory response to adenovirus vectors. Gene Ther. 10, 935–940.

    Article  CAS  PubMed  Google Scholar 

  • Malatack, J.J., Consolini, D.M., and Bayever, E. (2003). The status of hematopoietic stem cell transplantation in lysosomal storage disease. Pediatr. Neurol. 29, 391–403.

    Article  PubMed  Google Scholar 

  • Martin, R., Beck, M., Eng, C., Giugliani, R., Harmatz, P., Munoz, V., and Muenzer, J. (2008). Recognition and diagnosis of mucopolysaccharidosis II (Hunter syndrome). Pediatrics 121, e377–386.

    Article  PubMed  Google Scholar 

  • Muenzer, J., Lamsa, J.C., Garcia, A., Dacosta, J., Garcia, J., and Treco, D.A. (2002). Enzyme replacement therapy in mucopolysaccharidosis type II (Hunter syndrome): a preliminary report. Acta Paediatr. 91, 98–99.

    Article  CAS  Google Scholar 

  • Muruve, D.A. (2004). The innate immune response to adenovirus vectors. Hum. Gene Ther. 15, 1157–1166.

    Article  CAS  PubMed  Google Scholar 

  • Neufeld, E.F. (1991). Lysosomal storage diseases. Annu. Rev. Biochem. 60, 257–280.

    Article  CAS  PubMed  Google Scholar 

  • Oh, H.J., Park, E.S., Kang, S., Jo, I., and Jung, S.C. (2004). Longterm enzymatic and phenotypic correction in the phenylketonuria mouse model by adeno-associated virus vectormediated gene transfer. Pediatr. Res. 56, 278–284.

    Article  CAS  PubMed  Google Scholar 

  • Ohshima, T., Murray, G.J., Swaim, W.D., Longenecker, G., Quirk, J.M., Cardarelli, C.O., Sugimoto, Y., Pastan, I., Gottesman, M.M., Brady, R.O., et al. (1997). alpha-Galactosidase A deficient mice: a model of Fabry disease. Proc. Natl. Acad. Sci. USA 94, 2540–2544.

    Article  CAS  PubMed  Google Scholar 

  • Peters, C., and Krivit, W. (2000). Hematopoietic cell transplantation for mucopolysaccharidosis IIB (Hunter syndrome). Bone Marrow Transplant. 25, 1097–1099.

    Article  CAS  PubMed  Google Scholar 

  • Sly, W.S., Vogler, C., Grubb, J.H., Levy, B., Galvin, N., Tan, Y., Nishioka, T., and Tomatsu, S. (2006). Enzyme therapy in mannose receptor-null mucopolysaccharidosis VII mice defines roles for the mannose 6-phosphate and mannose receptors. Proc. Natl. Acad. Sci. USA 103, 15172–15177.

    Article  CAS  PubMed  Google Scholar 

  • Tomanin, R., and Scarpa, M. (2004). Why do we need new gene therapy viral vectors? Characteristics, limitations and future perspectives of viral vector transduction. Curr. Gene Ther. 4, 357–372.

    CAS  PubMed  Google Scholar 

  • Tomatsu, S., Orii, K.O., Vogler, C., Nakayama, J., Levy, B., Grubb, J.H., Gutierrez, M.A., Shim, S., Yamaguchi, S., Nishioka, T., et al. (2003). Mouse model of N-acetylgalactosamine-6-sulfate sulfatase deficiency (Galns−/−) produced by targeted disruption of the gene defective in Morquio A disease. Hum. Mol. Genet. 12, 3349–3358.

    Article  CAS  PubMed  Google Scholar 

  • Vellodi, A., Young, E., Cooper, A., Lidchi, V., Winchester, B., and Wraith, J.E. (1999). Long-term follow-up following bone marrow transplantation for Hunter disease. J. Inherit. Metab. Dis. 22, 638–648.

    Article  CAS  PubMed  Google Scholar 

  • Voznyi, Y.V., Keulemans, J.L., and van Diggelen, O.P. (2001). A fluorimetric enzyme assay for the diagnosis of MPS II (Hunter disease). J. Inherit. Metab. Dis. 24, 675–680.

    Article  CAS  PubMed  Google Scholar 

  • Whitley, C.B., McIvor, R.S., Aronovich, E.L., Berry, S.A., Blazar, B.R., Burger, S.R., Kersey, J.H., King, R.A., Faras, A.J., Latchaw, R.E., et al. (1996). Retroviral-mediated transfer of the iduronate-2-sulfatase gene into lymphocytes for treatment of mild Hunter syndrome (mucopolysaccharidosis type II). Hum. Gene Ther. 7, 537–549.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Affiliations

  1. Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 135-710, Korea

    Su Jin Kim & Dong-Kyu Jin

  2. Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul, 158-710, Korea

    Sung-Chul Jung, Eun-Sook Park & Eun Nam Choi

  3. Clinical Research Center, Samsung Biomedical Research Institute, Seoul, 135-710, Korea

    Chi Hwa Kim

Authors
  1. Sung-Chul Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eun-Sook Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eun Nam Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chi Hwa Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Su Jin Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dong-Kyu Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dong-Kyu Jin.

About this article

Cite this article

Jung, SC., Park, ES., Choi, E.N. et al. Characterization of a novel mucopolysaccharidosis type II mouse model and recombinant AAV2/8 vector-mediated gene therapy. Mol Cells 30, 13–18 (2010). https://doi.org/10.1007/s10059-010-0083-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10059-010-0083-2

Keywords

  • adeno-associated virus
  • gene therapy
  • hunter syndrome
  • iduronate-2-sulfatase
  • MPS II mouse model