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:

Encapsulated engineered myoblasts can cure Hurler syndrome: preclinical experiments in the mouse model

Gene Therapy volume 19, pages 355–364 (2012)Cite this article

Abstract

Mucopolysaccharidosis type I (MPSI) is an autosomic recessive, lysosomal storage disorder due to the deficit of the enzyme α-L-iduronidase (IDUA). The disease accounts for a general impairment of tissue and organ functions, mainly including heart disease, corneal clouding, organomegaly, skeletal malformations and joint stiffness. Neurological deterioration affects the severe forms. Both haemopoietic stem cell transplantation and enzyme replacement therapy can be applied to the treatment of the disorder; however, they both present several limitations. Thus, the search for alternative strategies to complement the present procedures is highly desirable. A murine myoblast cell line engineered to overexpress IDUA was generated and enclosed in alginate microcapsules, which were intra-peritoneally implanted in the MPSI mouse model. Plasma and tissue enzyme activity induced by the treatment and urinary and tissue glycosaminoglycan content were monitored in the animals, progressively sacrificed up to 4 months after implantation. Significant induction of enzyme activity and reduction of glycosaminoglycan accumulation were detected in the implanted animals, complete normalization of deposits was achieved in two animals. Intra-peritoneal implantation of alginate microcapsule confirms to be a valid approach as an endogenous enzyme replacement procedure.

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
Figure 9

Similar content being viewed by others

References

  1. Neufeld EF, Muenzer J . The mucopolysaccharidoses. In: The Metabolic and Molecular Bases of Inherited Disease, Vol. 3. McGraw-Hill Professional Publishing: New York, 2001, pp 3421–3452.

    Google Scholar 

  2. Illsinger S, Lucke T, Hartmann H, Mengel E, Muller-Forell W, Donnerstag F et al. Scheie syndrome: enzyme replacement therapy does not prevent progression of cervical myelopathy due to spinal cord compression. J Inherit Metab Dis. Short Report #190 (2009), Published online 4 November 2009; doi:10.1007/s10545-009-1265-y.

  3. Hobbs JR, Hugh-Jones K, Barrett AJ, Byrom N, Chambers D, Henry K et al. Reversal of clinical features of Hurler's disease and biochemical improvement after treatment by bone-marrow transplantation. Lancet 1981; 2: 709–712.

    Article  CAS  Google Scholar 

  4. Peters C, Steward CG . Hematopoietic cell transplantation for inherited metabolic diseases: an overview of outcomes and practice guidelines. Bone Marrow Transplant 2003; 31: 229–239.

    Article  CAS  Google Scholar 

  5. Wraith JE . Enzyme replacement therapy in mucopolysaccharidosis type I: progress and emerging difficulties. J Inherit Metab Dis 2001; 24: 245–250.

    Article  CAS  Google Scholar 

  6. Wraith JE, Beck M, Lane R, van der Ploeg A, Shapiro E, Xue Y et al. Enzyme replacement therapy in patients who have mucopolysaccharidosis I and are younger than 5 years: results of a multinational study of recombinant human alpha-L-iduronidase (laronidase). Pediatrics 2007; 120: e37–e46.

    Article  Google Scholar 

  7. Messina C, Rampazzo A, Cesaro S, Monciotti C, Gasparotto N, Tomanin R et al. Eighteen-year follow-up of the first Italian MPSI patient treated with bone marrow transplantation. Bone Marrow Transplant 2008; 41: 905–906.

    Article  CAS  Google Scholar 

  8. Clarke LA . Mucopolysaccharidosis Type I. In: Pagon RA, Bird TD, Dolan CR, Stephens K (eds). GeneReviews. University of Washington, Seattle: Seattle (WA), 1993.

    Google Scholar 

  9. Platt FM, Lachmann RH . Treating lysosomal storage disorders: current practice and future prospects. Biochim Biophys Acta 2009; 1793: 737–745.

    Article  CAS  Google Scholar 

  10. Chang PL . Microcapsules as bio-organs for somatic gene therapy. Ann NY Acad Sci 1997; 831: 461–473.

    Article  CAS  Google Scholar 

  11. 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  Google Scholar 

  12. Hernandez RM, Orive G, Murua A, Pedraz JL . Microcapsules and microcarriers for in situ cell delivery. Adv Drug Deliv Rev 2010; 62: 711–730.

    Article  CAS  Google Scholar 

  13. Barsoum SC, Milgram W, Mackay W, Coblentz C, Delaney KH, Kwiecien JM et al. Delivery of recombinant gene product to canine brain with the use of microencapsulation. J Lab Clin Med 2003; 142: 399–413.

    Article  CAS  Google Scholar 

  14. Friso A, Tomanin R, Alba S, Gasparotto N, Puicher EP, Fusco M et al. Reduction of GAG storage in MPS II mouse model following implantation of encapsulated recombinant myoblasts. J Gene Med 2005; 7: 1482–1491.

    Article  CAS  Google Scholar 

  15. Ohmi K, Greenberg DS, Rajavel KS, Ryazantsev S, Li HH, Neufeld EF . Activated microglia in cortex of mouse models of mucopolysaccharidoses I and IIIB. Proc Natl Acad Sci USA 2003; 100: 1902–1907.

    Article  CAS  Google Scholar 

  16. Wen J, Vargas AG, Ofosu FA, Hortelano G . Sustained and therapeutic levels of human factor IX in hemophilia B mice implanted with microcapsules: key role of encapsulated cells. J Gene Med 2006; 8: 362–369.

    Article  CAS  Google Scholar 

  17. Muenzer J, Fisher A . Advances in the treatment of mucopolysaccharidosis type I. N Engl J Med 2004; 350: 1932–1934.

    Article  CAS  Google Scholar 

  18. Desnick RJ . Enzyme replacement and enhancement therapies for lysosomal diseases. J Inherit Metab Dis 2004; 27: 385–410.

    Article  CAS  Google Scholar 

  19. Herati RS, Ma X, Tittiger M, Ohlemiller KK, Kovacs A, Ponder KP . Improved retroviral vector design results in sustained expression after adult gene therapy in mucopolysaccharidosis I mice. J Gene Med 2008; 10: 972–982.

    Article  CAS  Google Scholar 

  20. Mercimek-Mahmutoglu S, Reilly C, Human D, Waters PJ, Stoeckler-Ipsiroglu S . Progression of organ manifestations upon enzyme replacement therapy in a patient with mucopolysaccharidosis type I/Hurler. World J Pediatr 2009; 5: 319–321.

    Article  Google Scholar 

  21. Kakkis ED, Schuchman E, He X, Wan Q, Kania S, Wiemelt S et al. Enzyme replacement therapy in feline mucopolysaccharidosis I. Mol Genet Metab 2001; 72: 199–208.

    Article  CAS  Google Scholar 

  22. Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 (Text with EEA relevance). OJ 2007; L324: 121–137.

  23. Food and Drug Administration. Application of current statutory authorities to human somatic cell therapy products and gene therapy products. Fed Regist 1993; 58: 53248–53251.

    Google Scholar 

  24. de Vos P, Bucko M, Gemeiner P, Navratil M, Svitel J, Faas M et al. Multiscale requirements for bioencapsulation in medicine and biotechnology. Biomaterials 2009; 30: 2559–2570.

    Article  CAS  Google Scholar 

  25. Montgomery DL, Shiver JW, Leander KR, Perry HC, Friedman A, Martinez D et al. Heterologous and homologous protection against influenza A by DNA vaccination: optimization of DNA vectors. DNA Cell Biol 1993; 12: 777–783.

    Article  CAS  Google Scholar 

  26. Hortelano G, Al-Hendy A, Ofosu FA, Chang PL . Delivery of human factor IX in mice by encapsulated recombinant myoblasts: a novel approach towards allogeneic gene therapy of hemophilia B. Blood 1996; 87: 5095–5103.

    CAS  PubMed  Google Scholar 

  27. Di Domenico C, Villani GR, Di Napoli D, Reyero EG, Lombardo A, Naldini L et al. Gene therapy for a mucopolysaccharidosis type I murine model with lentiviral-IDUA vector. Hum Gene Ther 2005; 16: 81–90.

    Article  CAS  Google Scholar 

  28. 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  Google Scholar 

  29. Bjornsson S . Simultaneous preparation and quantitation of proteoglycans by precipitation with alcian blue. Anal Biochem 1993; 210: 282–291.

    Article  CAS  Google Scholar 

  30. Whitley CB, Ridnour MD, Draper KA, Dutton CM, Neglia JP . Diagnostic test for mucopolysaccharidosis. I. Direct method for quantifying excessive urinary glycosaminoglycan excretion. Clin Chem 1989; 35: 374–379.

    CAS  PubMed  Google Scholar 

  31. de Jong JG, Wevers RA, Liebrand-van Sambeek R . Measuring urinary glycosaminoglycans in the presence of protein: an improved screening procedure for mucopolysaccharidoses based on dimethylmethylene blue. Clin Chem 1992; 38: 803–807.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We wish to thank Elizabeth Neufeld (UCLA, CA, USA) and JM Heard (Pasteur Institute, Paris, France) for kindly providing the mouse model, E Kakkis (BioMarin, CA, USA) for anti-IDUA mouse serum, Jianping Wen (McMaster University, Hamilton, Ontario, Canada) for encapsulating C2C12-IDUA engineered cells. The project was funded by the Italian Ministry of Health (PRIN 2006, Grant no. 2006064337_002) and by the Italian Mucopolysaccharidosis Association (AIMPS). We also acknowledge funding from Canadian Blood Services to GH.

Author information

Author notes

  1. E Piller Puicher and R Tomanin: These authors contributed equally to this work.

Authors and Affiliations

  1. Centre for Rare Diseases and Department of Pediatrics, Gene Therapy Laboratory, University of Padova, Padova, Italy

    E Piller Puicher, R Tomanin, M Salvalaio, A Friso & M Scarpa

  2. Department of Pathology & Molecular Medicine, McMaster University, Hamilton, ON, Canada

    G Hortelano

  3. Department of Biochemistry, University of Padova, Padova, Italy

    O Marin

Authors
  1. E Piller Puicher
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R Tomanin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Salvalaio
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Friso
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G Hortelano
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. O Marin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Scarpa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Scarpa.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Piller Puicher, E., Tomanin, R., Salvalaio, M. et al. Encapsulated engineered myoblasts can cure Hurler syndrome: preclinical experiments in the mouse model. Gene Ther 19, 355–364 (2012). https://doi.org/10.1038/gt.2011.94

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gt.2011.94

Keywords

This article is cited by

Search

Advanced search

Quick links