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Prevention of systemic clinical disease in MPS VII mice following AAV-mediated neonatal gene transfer

Gene Therapy volume 8, pages 1291–1298 (2001)Cite this article

Abstract

For many inborn errors of metabolism, early treatment is critical to prevent long-term developmental sequelae. We have previously shown that systemic treatment of neonatal mucopolysaccharidosis type VII (MPS VII) mice with recombinant adeno-associated virus (AAV) vectors results in relatively long-term expression of β-glucuronidase (GUSB) in multiple tissues, and a reduction in lysosomal storage. Here, we demonstrate that therapeutic levels of enzyme persist for at least 1 year following a single intravenous injection of virus in neonatal MPS VII mice. The level and distribution of GUSB expression achieved is sufficient to prevent the development of many aspects of clinical disease over the life of the animal. Following treatment, bone lengths, weights and retinal function were maintained at nearly normal levels throughout the life of the animal. In addition, significant improvements in survival and auditory function were seen in AAV-treated MPS VII mice when compared with untreated mutant siblings. These data suggest that AAV-mediated gene transfer in the neonatal period can lead to prevention of many of the clinical symptoms associated with MPS VII in the murine model of this disease.

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References

  1. Sly WS, Quinton BA, McAlister WH, Rimoin DL . Beta glucuronidase deficiency: report of clinical, radiologic, and biochemical features of a new mucopolysaccharidosis J Pediatr 1973 82: 249–257

    Article  CAS  PubMed  Google Scholar 

  2. Neufeld E, Fratantoni J . Inborn errors of mucopolysaccharide metabolism Science 1970 169: 141–146

    Article  CAS  PubMed  Google Scholar 

  3. Birkenmeier EH et al. Murine mucopolysaccharidosis type VII. Characterization of a mouse with beta-glucuronidase deficiency J Clin Invest 1989 83: 1258–1256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Haskins ME et al. Hepatic storage of glycosaminoglycans in feline and canine models of mucopolysaccharidoses I, VI, and VII Vet Pathol 1992 29: 112–119

    Article  CAS  PubMed  Google Scholar 

  5. Sands MS, Birkenmeier EH . A single base pair deletion in the β-glucuronidase gene accounts for the phenotype in murine mucopolysaccharidosis type VII Proc Natl Acad Sci USA 1993 90: 6567–6572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Birkenmeier EH et al. Increased life span and correction of metabolic defects in murine mucopolysaccharidosis type VII after syngeneic bone marrow transplantation Blood 1991 78: 3081–3092

    CAS  PubMed  Google Scholar 

  7. Kornfeld S . Structure and function of the mannose 6-phosphate/insulinlike growth factor II receptors Annu Rev Biochem 1992 61: 307–330

    Article  CAS  PubMed  Google Scholar 

  8. Vogler C et al. Enzyme replacement with recombinant beta-glucuronidase in the newborn mucopolysaccharidosis type VII mouse Pediatr Res 1993 34: 837–840

    Article  CAS  PubMed  Google Scholar 

  9. Sands MS et al. Enzyme replacement therapy for murine mucopolysaccharidosis type VII J Clin Invest 1994 93: 2324–2331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. O'Connor LH et al. Enzyme replacement therapy for murine mucopolysaccharidosis type VII leads to improvements in behavior and auditory function J Clin Invest 1998 101: 1394–1400

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Vogler C et al. 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 

  12. Sands MS et al. Treatment of murine mucopolysaccharidosis type VII by syngeneic bone marrow transplantation in neonates Lab Invest 1993 68: 676–686

    CAS  PubMed  Google Scholar 

  13. Sands MS et al. Murine mucopolysaccharidosis type VII: long term therapeutic effects of enzyme replacement and enzyme replacement followed by bone marrow transplantation J Clin Invest 1997 99: 1596–1605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Vogler C et al. Enzyme replacement in murine mucopolysaccharidosis type VII: neuronal and glial response to β-glucuronidase requires early initiation of enzyme replacement therapy Pediatr Res 1999 45: 838–844

    Article  CAS  PubMed  Google Scholar 

  15. Ohlemiller KK et al. Retinal function is improved in a murine model of a lysosomal storage disease following bone marrow transplantation Exp Eye Res 2000 71: 469–481

    Article  CAS  PubMed  Google Scholar 

  16. Sands MS et al. Syngeneic bone marrow transplantation reduces the hearing loss associated with murine mucopolysaccharidosis type VII Blood 1995 86: 2033–2040

    CAS  PubMed  Google Scholar 

  17. 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 

  18. Wolfe JH et al. Reversal of pathology in murine mucopolysaccharidosis type VII by somatic cell gene transfer Nature 1992 360: 749–753

    Article  CAS  PubMed  Google Scholar 

  19. Linden RM et al. Site-specific integration by adeno-associated virus Proc Natl Acad Sci USA 1996 93: 11288–11294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hong G, Ward P, Berns KI . Intermediates of adeno-associated virus DNA replication in vitro J Virol 1994 68: 2011–2015

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Fisher KJ et al. Recombinant adeno-associated virus for muscle directed gene therapy Nat Med 1997 3: 306–312

    Article  CAS  PubMed  Google Scholar 

  22. Jooss K, Yang Y, Fisher KJ, Wilson JM . Transduction of dendritic cells by DNA viral vectors directs the immune response to transgene products in muscle fibers J Virol 1998 72: 4212–4223

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Daly TM et al. Neonatal intramuscular injection with recombinant adeno-associated virus results in prolonged β-glucuronidase expression in situ and correction of liver pathology in mucopolysaccharidosis type VII mice Hum Gene Ther 1999 10: 85–94

    Article  CAS  PubMed  Google Scholar 

  24. Kyle JW et al. Correction of murine mucopolysaccharidosis type VII by a human β-glucuronidase transgene Proc Natl Acad Sci USA 1990 87: 3914–3918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wolfe JH et al. High level expression and export of β-glucuronidase from MPS VII cells corrected by a double copy retroviral vector Gene Therapy 1995 2: 70–78

    CAS  PubMed  Google Scholar 

  26. Berry CL et al. Pathology of the ear in murine mucopolysaccharidosis type VII. Morphologic correlates of hearing loss Lab Invest 1994 71: 438–445

    CAS  PubMed  Google Scholar 

  27. Soper BW et al. Enzyme replacement therapy improves reproductive performance in mucopolysaccharidosis type VII mice but does not prevent postnatal losses Pediatr Res 1999 45: 180–186

    Article  CAS  PubMed  Google Scholar 

  28. Daly TM, Lorenz RG, Sands MS . Abnormal immune function in vivo in a murine model of lysosomal storage disease Pediatr Res 2000 47: 757–762

    Article  CAS  PubMed  Google Scholar 

  29. Grimm D, Kern A, Rittner K, Kleinschmidt JA . Novel tools for production and purification of recombinant adeno-associated viral vectors Hum Gene Ther 1998 9: 2745–2760

    Article  CAS  PubMed  Google Scholar 

  30. Zolotukhin S 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 

  31. Wolfe JH, Sands MS . Murine mucopolysaccharidosis type VII: a model system for somatic gene therapy of the central nervous system In: Lowenstein P, Enquist L (eds) Gene Therapy into Neurones, towards Gene Therapy of Neurological Disorders J Wiley and Sons: UK 1996 pp 263–274

    Google Scholar 

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

    CAS  Google Scholar 

  33. Ohlemiller KK et al. Targeted deletion of the cytosolic Cu/Zn-superoxide dismutase gene (Sod1) increases susceptibility to noise-induced hearing loss Audiol Neurootol 1998 4: 237–246

    Article  Google Scholar 

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Acknowledgements

This work was supported in part by NIH grants DK53920 (MSS) and HD35671 (MSS, CAV), the National MPS Society Raymond Bryan IV Fellowship (TMD), the Spencer T and Anna W Olin Foundation (KKO) and the Edward Mallinckrodt Jr Foundation (KKO). Stocks of recombinant AAV were produced at the Gene Therapy Center of the University of Florida, and supported by NIH grants HL59412 and P01NS36302 to Dr Nicholas Muzyczka. All animal procedures were approved and performed in accordance with the guidelines established by the Institutional Animal Care and Use Committee of Washington University.

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Authors and Affiliations

  1. Division of Laboratory Medicine, Washington University School of Medicine, St Louis, MO, USA

    TM Daly

  2. Research Department, Central Institute for the Deaf, St Louis, MO, USA

    KK Ohlemiller

  3. Division of Internal Medicine, Washington University School of Medicine, St Louis, MO, USA

    MS Roberts & MS Sands

  4. Division of Genetics, Washington University School of Medicine, St Louis, MO, USA

    MS Roberts & MS Sands

  5. Department of Pathology, St Louis University School of Medicine, St Louis, MO, USA

    CA Vogler

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Daly, T., Ohlemiller, K., Roberts, M. et al. Prevention of systemic clinical disease in MPS VII mice following AAV-mediated neonatal gene transfer. Gene Ther 8, 1291–1298 (2001). https://doi.org/10.1038/sj.gt.3301420

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