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:

Widespread biochemical correction of murine mucopolysaccharidosis type VII pathology by liver hydrodynamic plasmid delivery

Gene Therapy volume 16, pages 746–756 (2009)Cite this article

Abstract

Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by a deficiency of the acid hydrolase β-glucuronidase. MPS VII mice develop progressive lysosomal accumulation of glycosaminoglycans (GAGs) within multiple organs, including the brain. Using this animal model, we compared two plasmid gene administration techniques: muscle electrotransfer and liver-directed transfer using hydrodynamic injection. We have evaluated both the expression kinetics and the biodistribution of β-glucuronidase activity after gene transfer, as well as the correction of biochemical abnormalities in various organs. This study shows that MPS VII mice treated with a plasmid-bearing mouse β-glucuronidase cDNA, acquire the ability to produce the β-glucuronidase enzyme for an extended period of time. The liver seemed to be more appropriate than the muscle as a target organ to enable enzyme secretion into the systemic circulation. A beneficial effect on the MPS VII pathology was also observed, as liver-directed gene transfer led to the correction of secondary enzymatic elevations and to the reduction of GAGs storage in peripheral tissues and brain, as well as to histological correction in many tissues. This work is one of the first examples showing that non-viral plasmid DNA delivery can lead to improvements in both peripheral and brain manifestations of MPS VII disease. It confirms the potential of non-viral systemic gene transfer strategy in neurological lysosomal disorders.

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

Similar content being viewed by others

References

  1. Neufeld EF, Muenzer J . The mucopolysaccharidosis. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds). Metabol Mol Bases Inherit Dis. MacGraw-Hill: New York, 2001, pp 3421–3452.

    Google Scholar 

  2. Birkenmeier EH, Davisson MT, Beamer WG, Ganschow RE, Vogler CA, Gwynn B et al. Murine mucopolysaccharidosis type VII. Characterization of a mouse with beta-glucuronidase deficiency. J Clin Invest 1989; 83: 1258–1266.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Vogler C, Barker J, Sands MS, Levy B, Galvin N, Sly WS et al. Murine mucopolysaccharidosis VII: impact of therapies on the phenotype, clinical course, and pathology in a model of a lysosomal storage disease. Pediatr Dev Pathol 2001; 4: 421–433.

    Article  CAS  PubMed  Google Scholar 

  4. Vogler C, Levy B, Galvin N, Lessard M, Soper B, Barker J et al. Early onset of lysosomal storage disease in a murine model of mucopolysaccharidosis type VII: undegraded substrate accumulates in many tissues in the fetus and very young MPS VII mouse. Pediatr Dev Pathol 2005; 8: 453–462.

    Article  CAS  PubMed  Google Scholar 

  5. Neufeld EF . Lysosomal storage diseases. Annu Rev Biochem 1991; 60: 257–280.

    Article  CAS  PubMed  Google Scholar 

  6. Watson GL, Sayles JN, Chen C, Elliger SS, Elliger CA, Raju NR et al. Treatment of lysosomal storage disease in MPS VII mice using a recombinant adeno-associated virus. Gene Therapy 1998; 5: 1642–1649.

    Article  CAS  PubMed  Google Scholar 

  7. Daly TM, Sands MS . Gene therapy for lysosomal storage diseases. Expert Opin Investig Drugs 1998; 7: 1673–1682.

    Article  CAS  PubMed  Google Scholar 

  8. Moullier P, Bohl D, Heard JM, Danos O . Correction of lysosomal storage in the liver and spleen of MPS VII mice by implantation of genetically modified skin fibroblasts. Nat Genet 1993; 4: 154–159.

    Article  CAS  PubMed  Google Scholar 

  9. Sands MS, Vogler C, Kyle JW, Grubb JH, Levy B, Galvin N et al. Enzyme replacement therapy for murine mucopolysaccharidosis type VII. J Clin Invest 1994; 93: 2324–2331.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Wolfe JH, Sands MS, Harel N, Weil MA, Parente MK, Polesky AC et al. Gene transfer of low levels of beta-glucuronidase corrects hepatic lysosomal storage in a large animal model of mucopolysaccharidosis VII. Mol Ther 2000; 2: 552–561.

    Article  CAS  PubMed  Google Scholar 

  11. Donsante A, Levy B, Vogler C, Sands MS . Clinical response to persistent, low-level beta-glucuronidase expression in the murine model of mucopolysaccharidosis type VII. J Inherit Metab Dis 2007; 30: 227–238.

    Article  CAS  PubMed  Google Scholar 

  12. Sands MS, Davidson BL . Gene therapy for lysosomal storage diseases. Mol Ther 2006; 13: 839–849.

    Article  CAS  PubMed  Google Scholar 

  13. Cheng SH, Smith AE . Gene therapy progress and prospects: gene therapy of lysosomal storage disorders. Gene Therapy 2003; 10: 1275–1281.

    Article  CAS  PubMed  Google Scholar 

  14. Mir LM, Bureau MF, Gehl J, Rangara R, Rouy D, Caillaud JM et al. High-efficiency gene transfer into skeletal muscle mediated by electric pulses. Proc Natl Acad Sci USA 1999; 96: 4262–4267.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Scherman D . Towards non-viral gene therapy. Bull Acad Natl Med 2001; 185: 1683–1697.

    CAS  PubMed  Google Scholar 

  16. Suda T, Liu D . Hydrodynamic gene delivery: its principles and applications. Mol Ther 2007; 15: 2063–2069.

    Article  CAS  PubMed  Google Scholar 

  17. Herweijer H, Wolff JA . Gene therapy progress and prospects: hydrodynamic gene delivery. Gene Therapy 2007; 14: 99–107.

    Article  CAS  PubMed  Google Scholar 

  18. Aronovich EL, Bell JB, Belur LR, Gunther R, Koniar B, Erickson DC et al. Prolonged expression of a lysosomal enzyme in mouse liver after sleeping beauty transposon-mediated gene delivery: implications for non-viral gene therapy of mucopolysaccharidoses. J Gene Med 2007; 9: 403–415.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Kay MA, Baley P, Rothenberg S, Leland F, Fleming L, Ponder KP et al. Expression of human alpha 1-antitrypsin in dogs after autologous transplantation of retroviral transduced hepatocytes. Proc Natl Acad Sci USA 1992; 89: 89–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Snyder RO, Miao CH, Patijn GA, Spratt SK, Danos O, Nagy D et al. Persistent and therapeutic concentrations of human factor IX in mice after hepatic gene transfer of recombinant AAV vectors. Nat Genet 1997; 16: 270–276.

    Article  CAS  PubMed  Google Scholar 

  21. Birkenmeier EH, Barker JE, Vogler CA, Kyle JW, Sly WS, Gwynn B 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 

  22. Xu L, Mango RL, Sands MS, Haskins ME, Ellinwood NM, Ponder KP . Evaluation of pathological manifestations of disease in mucopolysaccharidosis VII mice after neonatal hepatic gene therapy. Mol Ther 2002; 6: 745–758.

    Article  CAS  PubMed  Google Scholar 

  23. Ross CJ, Bastedo L, Maier SA, Sands MS, Chang PL . Treatment of a lysosomal storage disease, mucopolysaccharidosis VII, with microencapsulated recombinant cells. Hum Gene Ther 2000; 11: 2117–2127.

    Article  CAS  PubMed  Google Scholar 

  24. Bettan M, Emmanuel F, Darteil R, Caillaud JM, Soubrier F, Delaere P et al. High-level protein secretion into blood circulation after electric pulse-mediated gene transfer into skeletal muscle. Mol Ther 2000; 2: 204–210.

    Article  CAS  PubMed  Google Scholar 

  25. Raben N, Lu N, Nagaraju K, Rivera Y, Lee A, Yan B et al. Conditional tissue-specific expression of the acid alpha-glucosidase (GAA) gene in the GAA knockout mice: implications for therapy. Hum Mol Genet 2001; 10: 2039–2047.

    Article  CAS  PubMed  Google Scholar 

  26. Tessitore A, Faella A, O’Malley T, Cotugno G, Doria M, Kunieda T et al. Biochemical, pathological, and skeletal improvement of mucopolysaccharidosis VI after gene transfer to liver but not to muscle. Mol Ther 2008; 16: 30–37.

    Article  CAS  PubMed  Google Scholar 

  27. Martin-Touaux E, Puech JP, Château D, Emiliani C, Kremer EJ, Raben N et al. Muscle as a putative producer of acid alpha-glucosidase for glycogenosis type II gene therapy. Hum Mol Genet 2002; 11: 1637–1645.

    Article  CAS  PubMed  Google Scholar 

  28. Takahashi H, Hirai Y, Migita M, Seino Y, Fukuda Y, Sakuraba H et al. Long-term systemic therapy of Fabry disease in a knockout mouse by adeno-associated virus-mediated muscle-directed gene transfer. Proc Natl Acad Sci USA 2002; 99: 13777–13782.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Naffakh N, Pinset C, Montarras D, Li Z, Paulin D, Danos O et al. Long-term secretion of therapeutic proteins from genetically modified skeletal muscles. Hum Gene Ther 1996; 7: 11–21.

    Article  CAS  PubMed  Google Scholar 

  30. Kreiss P, Bettan M, Crouzet J, Scherman D . Erythropoietin secretion and physiological effect in mouse after intramuscular plasmid DNA electrotransfer. J Gene Med 1999; 1: 245–250.

    Article  CAS  PubMed  Google Scholar 

  31. Tomanin R, Friso A, Alba S, Piller Puicher E, Mennuni C, La Monica N et al. Non-viral transfer approaches for the gene therapy of mucopolysaccharidosis type II (Hunter syndrome). Acta Paediatr Suppl 2002; 91: 100–104.

    Article  CAS  PubMed  Google Scholar 

  32. Sferra TJ, Backstrom K, Wang C, Rennard R, Miller M, Hu Y et al. Widespread correction of lysosomal storage following intrahepatic injection of a recombinant adeno-associated virus in the adult MPS VII mouse. Mol Ther 2004; 10: 478–491.

    Article  CAS  PubMed  Google Scholar 

  33. 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 

  34. Chen ZY, Riu E, He CY, Xu H, Kay MA . Silencing of episomal transgene expression in liver by plasmid bacterial backbone DNA is independent of CpG methylation. Mol Ther 2008; 16: 548–556.

    Article  CAS  PubMed  Google Scholar 

  35. Hodges BL, Taylor KM, Joseph MF, Bourgeois SA, Scheule RK . Long term transgene expression from plasmid DNA gene therapy vectors is negatively affected by CpG dinucleotides. Mol Ther 2004; 10: 269–278.

    Article  CAS  PubMed  Google Scholar 

  36. 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 

  37. Urayama A, Grubb JH, Sly WS, Banks WA . Developmentally regulated mannose 6-phosphate receptor-mediated transport of a lysosomal enzyme across the blood–brain barrier. Proc Natl Acad Sci USA 2004; 101: 12658–12663.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Urayama A, Grubb JH, Sly WS, Banks WA . Mannose 6-phosphate receptor-mediated transport of sulfamidase across the blood-brain barrier in the newborn mouse. Mol Ther 2008; 16: 1261–1266.

    Article  CAS  PubMed  Google Scholar 

  39. Vogler C, Levy B, Grubb JH, Galvin N, Tan Y, Kakkis E et al. Overcoming the blood-brain barrier with high-dose enzyme replacement therapy in murine mucopolysaccharidosis VII. Proc Natl Acad Sci USA 2005; 102: 14777–14782.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Dunder U, Kaartinen V, Valtonen P, Väänänen E, Kosma VM, Heisterkamp N et al. Enzyme replacement therapy in a mouse model of aspartylglycosaminuria. FASEB J 2000; 14: 361–367.

    Article  CAS  PubMed  Google Scholar 

  41. Matzner U, Herbst E, Hedayati KK, Lüllmann-Rauch R, Wessig C, Schröder S et al. Enzyme replacement improves nervous system pathology and function in a mouse model for metachromatic leukodystrophy. Hum Mol Genet 2005; 14: 1139–1152.

    Article  CAS  PubMed  Google Scholar 

  42. Zhang X, Dong X, Sawyer GJ, Collins L, Fabre JW . Regional hydrodynamic gene delivery to the rat liver with physiological volumes of DNA solution. J Gene Med 2004; 6: 693–703.

    Article  CAS  PubMed  Google Scholar 

  43. Fabre JW, Grehan A, Whitehorne M, Sawyer GJ, Dong X, Salehi S et al. Hydrodynamic gene delivery to the pig liver via an isolated segment of the inferior vena cava. Gene Ther 2008; 15: 452–462.

    Article  CAS  PubMed  Google Scholar 

  44. Jacobs F, Snoeys J, Feng Y, Van Craeyveld E, Lievens J, Armentano D et al. Direct comparison of hepatocyte-specific expression cassettes following adenoviral and nonviral hydrodynamic gene transfer. Gene Therapy 2008; 15: 594–603.

    Article  CAS  PubMed  Google Scholar 

  45. Darquet AM, Rangara R, Kreiss P, Schwartz B, Naimi S, Delaère P et al. Minicircle: an improved DNA molecule for in vitro and in vivo gene transfer. Gene Therapy 1999; 6: 209–218.

    Article  CAS  PubMed  Google Scholar 

  46. Wooddell CI, Reppen T, Wolff JA, Herweijer H . Sustained liver-specific transgene expression from the albumin promoter in mice following hydrodynamic plasmid DNA delivery. J Gene Med 2008; 10: 551–563.

    Article  CAS  PubMed  Google Scholar 

  47. Argyros O, Wong SP, Niceta M, Waddington SN, Howe SJ, Coutelle C et al. Persistent episomal transgene expression in liver following delivery of a scaffold/matrix attachment region containing non-viral vector. Gene Therapy 2008; 15: 1593–1605.

    Article  CAS  PubMed  Google Scholar 

  48. Liu F, Song Y, Liu D . Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA. Gene Therapy 1999; 6: 1258–1266.

    Article  CAS  PubMed  Google Scholar 

  49. Zhang G, Budker V, Wolff JA . High levels of foreign gene expression in hepatocytes after tail vein injections of naked plasmid DNA. Hum Gene Ther 1999; 10: 1735–1737.

    Article  CAS  PubMed  Google Scholar 

  50. Wolfe JH, Sands MS . Murine mucopolysaccharidosis type VII: a model system for somatic gene therapy of the central nervous system. In: Enquist PR, Enquist LW (eds). Protocols for Gene Transfer in Neuroscience: Toward Gene Therapy of Neurologic Disorders. Wiley: Essex, 1996, pp 263–274.

    Google Scholar 

  51. Kyle JW, Grubb JH, Galvin N, Vogler C . Beta-glucuronidase (GUS) assay in animal tissue. In: Gallagher SR (ed). GUS Protocols: Using the GUS gene as a Reporter of Gene Expression. Academic Press: San Diego, 1992, pp 189–203.

    Chapter  Google Scholar 

Download references

Acknowledgements

We thank Dr B Soper for generously providing the gusmps/gusmps mice, as well as Dr J Grubb for kindly providing the murine β-glucuronidase protein. We thank also Dr J-M Caillaud (Biodoxis, Romainville, France) for his support in performing bright field microscopy histological analyses of tissues. This work was supported by European ‘MOLEDA’ STREP and European ‘CLINIGENE’ Network of Excellence. MR and AA received sponsorship from MOLEDA and CLINIGENE, respectively.

Author information

Author notes

  1. M Richard and A Arfi: The two authors contributed equally to this work.

Authors and Affiliations

  1. Institut de Sciences et Techniques du Médicament, Inserm, U640, Paris, France

    M Richard, A Arfi, J Seguin, C Gandolphe & D Scherman

  2. Institut de Chimie, CNRS, UMR8151, Paris, France

    M Richard, A Arfi, J Seguin, C Gandolphe & D Scherman

  3. Department of Therapeutic and Diagnostic Innovation, Chemical and Genetic Pharmacology Laboratory, Faculté de Pharmacie, Université Paris Descartes, Paris, France

    M Richard, A Arfi, J Seguin, C Gandolphe & D Scherman

  4. Friedel Department of Molecular Chemistry, Ecole Nationale Supérieure de Chimie de Paris, Paris, France

    M Richard, A Arfi, J Seguin, C Gandolphe & D Scherman

Authors
  1. M Richard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Arfi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Seguin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C Gandolphe
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D Scherman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D Scherman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Richard, M., Arfi, A., Seguin, J. et al. Widespread biochemical correction of murine mucopolysaccharidosis type VII pathology by liver hydrodynamic plasmid delivery. Gene Ther 16, 746–756 (2009). https://doi.org/10.1038/gt.2009.36

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gt.2009.36

Keywords

This article is cited by

Search

Advanced search

Quick links