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Subcutaneous implantation of microencapsulated cells overexpressing α-L-iduronidase for mucopolysaccharidosis type I treatment

  • Valeska Lizzi Lagranha
  • Barbara Zambiasi Martinelli
  • Guilherme Baldo
  • Giuseppe Ávila Testa
  • Talita Giacomet de Carvalho
  • Roberto Giugliani
  • Ursula Matte
Clinical Applications of Biomaterials Original Research
Part of the following topical collections:
  1. Clinical Applications of Biomaterials

Abstract

Mucopolysaccharidosis type I (MPS I) is caused by a deficiency of α-L-iduronidase (IDUA), resulting in accumulation of glycosaminoglycans (GAG) in lysosomes. Microencapsulation of recombinant cells is a promising gene/cell therapy approach that could overcome the limitations of the current available treatments. In the present study we produced alginate-poly-L-lysine-alginate (APA) microcapsules containing recombinant cells overexpressing IDUA, which were implanted in the subcutaneous space of MPS I mice in order to evaluate their potential effect as a treatment for this disease. APA microcapsules enclosing genetically modified Baby Hamster Kidney cells overexpressing IDUA were produced and implanted in the subcutaneous space of 4-month-old MPS I mice (Idua -/-). Treatment was performed using two cell concentrations: 8.3 × 107 and 8.3 × 106 cells/mL. Untreated MPS I and normal mice were used as controls. Microcapsules were retrieved and analyzed after treatment. Increased IDUA in the liver, kidney and heart was detected 24 h postimplantation. After 120 days, higher IDUA activity was detected in the liver, kidney and heart, in both groups, whereas GAG accumulation was reduced only in the high cell concentration group. Microcapsules analysis showed blood vessels around them, as well as inflammatory cells and a fibrotic layer. Microencapsulated cells were able to ameliorate some aspects of the disease, indicating their potential as a treatment. To achieve better performance of the microcapsules, improvements such as the modulation of inflammatory response are suggested.

Graphical Abstract

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Keywords

Hematopoietic Stem Cell Transplantation Enzyme Replacement Therapy Recombinant Cell High Cell Concentration Baby Hamster Kidney Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

APA

Alginate-poly-L-lysine-alginate

ERT

Enzyme replacement therapy

GAG

Glycosaminoglycans

HSCT

Hematopoietic stem cell transplantation

IDUA

Alpha-L-iduronidase

LSD

Lysosomal storage disorder

MPS I

Mucopolysaccharidosis type I

rBHKIdua

Recombinant BHK to overexpress IDUA

Notes

Acknowledgements

The authors are grateful to CNPq, CAPES and FIPE-HCPA for the financial support that allowed this research.

Compliance with ethical standards

Conflict of interest

The authors declare no competing conflict of interest.

References

  1. 1.
    Wraith JE, Jones S. Mucopolysaccharidosis type I. Pediatr Endocrinol Rev. 2014;12(Suppl 1):102–6.Google Scholar
  2. 2.
    Clarke La, Wraith JE, Beck M, Kolodny EH, Pastores GM, Muenzer J, et al. Longterm efficacy and safety of laronidase in the treatment of mucopolysaccharidosis I. Pediatrics. 2009;123:229–40.CrossRefGoogle Scholar
  3. 3.
    Giugliani R, Federhen A, Rojas MVM, Vieira T, Artigalás O, Pinto LL, et al. Mucopolysaccharidosis I, II, and VI: brief review and guidelines for treatment. Genet Mol Biol. 2010;33:589–604.CrossRefGoogle Scholar
  4. 4.
    Beck M, Arn P, Giugliani R, Muenzer J, Okuyama T, Taylor J, Fallet S. The natural history of MPS I: global perspectives from the MPS I Registry. Genet Med. 2014;16(10):759–65.CrossRefGoogle Scholar
  5. 5.
    Giugliani R, Federhen A, Vairo F, Vanzella C, Pasqualim G, da Silva LM, Giugliani L, de Boer AP, de Souza CF, Matte U, Baldo G. Emerging drugs for the treatment of mucopolysaccharidoses. Expert Opin Emerg Drugs. 2016;21(1):9–26.CrossRefGoogle Scholar
  6. 6.
    Boelens JJ, Prasad VK, Tolar J, Wynn RF, Peters C. Current international perspectives on hematopoietic stem cell transplantation for inherited metabolic disorders. Pediatr Clin North Am. 2010;57:123–45.CrossRefGoogle Scholar
  7. 7.
    Jameson E, Jones S, Remmington T. Enzyme replacement therapy with laronidase (Aldurazyme(®)) for treating mucopolysaccharidosis type I. Cochrane Database Syst Rev. 2016;1(4):CD009354.Google Scholar
  8. 8.
    Matte U, Lagranha VL, de Carvalho TG, Mayer FQ, Giugliani R. Cell microencapsulation: a potential tool for the treatment of neuronopathic lysosomal storage diseases. J Inherit Metab Dis. 2011;34:983–90.CrossRefGoogle Scholar
  9. 9.
    Giugliani R. Mucopolysacccharidoses: from understanding to treatment, acentury of discoveries. Genet Mol Biol. 2012;35(4 (Suppl)):924–31.CrossRefGoogle Scholar
  10. 10.
    Baldo G, Giugliani R, Matte U. Gene delivery strategies for the treatment of mucopolysaccharidoses. Expert Opin Drug Deliv. 2014;11:449–59.CrossRefGoogle Scholar
  11. 11.
    Noh H, Lee JI. Current and potential therapeutic strategies for mucopolysaccharidoses. J Clin Pharm Ther. 2014;39(3):215–24.CrossRefGoogle Scholar
  12. 12.
    Orive G, Tam SK, Pedraz JL, Hallé JP. Biocompatibility of alginate-poly-L-lysine microcapsules for cell therapy. Biomaterials. 2006;27(20):3691–700.CrossRefGoogle Scholar
  13. 13.
    Baldo G, Quoos Mayer F, Burin M, Carrillo-Farga J, Matte U, Giugliani R. Recombinant encapsulated cells overexpressing alpha-L-iduronidase correct enzyme deficiency in human mucopolysaccharidosis type I cells. Cells Tissues Organs. 2012;195:323–9.CrossRefGoogle Scholar
  14. 14.
    Baldo G, Mayer FQ, Martinelli B, Meyer FS, Burin M, Meurer L, et al. Intraperitoneal implant of recombinant encapsulated cells overexpressing alpha-Liduronidase partially corrects visceral pathology in mucopolysaccharidosis type I mice. Cytotherapy. 2012;14:860–7.CrossRefGoogle Scholar
  15. 15.
    Lagranha VL, de Carvalho TG, Giugliani R, Matte U. Treatment of MPS I mice with microencapsulated cells overexpressing IDUA: effect of the prednisolone administration. J Microencapsul. 2013;30(4):383–9.CrossRefGoogle Scholar
  16. 16.
    Consiglio A, Martino S, Dolcetta D, Cusella G, Conese M, Marchesini S, Benaglia G, Wrabetz L, Orlacchio A, Déglon N, Aebischer P, Severini GM, Bordignon C. Metabolic correction in oligodendrocytes derived from metachromatic leukodystrophy mouse model by using encapsulated recombinant myoblasts. J Neurol Sci. 2007;15(255(1–2)):7–16.CrossRefGoogle Scholar
  17. 17.
    Piller Puicher E, Tomanin R, Salvalaio M, Friso A, Hortelano G, Marin O, et al. Encapsulated engineered myoblasts can cure Hurler syndrome: preclinical experiments in the mouse model. Gene Ther. 2012;19:355–64.CrossRefGoogle Scholar
  18. 18.
    Paul A, Ge Y, Prakash S, Shum-Tim D. Microencapsulated stem cells for tissue repairing: implications in cell-based myocardial therapy. Regen Med. 2009;4:733–45.CrossRefGoogle Scholar
  19. 19.
    Blocki A, Beyer S, Dewavrin JY, Goralczyk A, Wang Y, Peh P, Ng M, Moonshi SS, Vuddagiri S, Raghunath M, Martinez EC, Bhakoo KK. Microcapsules engineered to support mesenchymal stem cell (MSC) survival and proliferation enable long-term retention of MSCs in infarcted myocardium. Biomaterials. 2015;53:12–24.CrossRefGoogle Scholar
  20. 20.
    Calafiore R, Basta G. Clinical application of microencapsulated islets: actual prospectives on progress and challenges. Adv Drug Deliv Rev. 2014;67-68:84–92.CrossRefGoogle Scholar
  21. 21.
    Song S, Roy S. Progress and challenges in macroencapsulation approaches for type 1 diabetes (T1D) treatment: cells, biomaterials, and devices. Biotechnol Bioeng. 2016;113(7):1381–402.CrossRefGoogle Scholar
  22. 22.
    Goren A, Gilert A, Meyron‐Holtz E. Alginate encapsulated cells secreting Fasligand reduce lymphoma carcinogenicity. Cancer Sci. 2012;103:116–24.CrossRefGoogle Scholar
  23. 23.
    Bhunchu S, Rojsitthisak P. Biopolymeric alginate-chitosan nanoparticles as drug delivery carriers for câncer therapy. Pharmazie. 2014;69(8):563–70.Google Scholar
  24. 24.
    Saenz del Burgo L, Compte M, Aceves M, Hernández RM, Sanz L, Álvarez-Vallina L, Pedraz JL. Microencapsulation of therapeutic bispecific antibodies producing cells: immunotherapeutic organoids for cancer management. J Drug Target. 2015;23(2):170–9.CrossRefGoogle Scholar
  25. 25.
    Garcia P, Youssef I, Utvik JK, Florent-Béchard S, Barthélémy V, MalaplateArmand C, et al. Ciliary neurotrophic factor cell-based delivery prevents synaptic impairment and improves memory in mouse models of Alzheimer’s disease. J Neurosci. 2010;30:7516–27.CrossRefGoogle Scholar
  26. 26.
    Emerich DF, Orive G, Thanos C, Tornoe J, Wahlberg LU. Encapsulated cell therapy for neurodegenerative diseases: from promise to product. Adv Drug Deliv Rev. 2014 Apr;67–68:131–41.CrossRefGoogle Scholar
  27. 27.
    Mayer FQ, Baldo G, de Carvalho TG, Lagranha VL, Giugliani R, Matte U. Effects of cryopreservation and hypothermic storage on cell viability and enzyme activity in recombinant encapsulated cells overexpressing alpha-L-iduronidase. Artif Organs. 2010;34:434–9.CrossRefGoogle Scholar
  28. 28.
    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;100:1902–7.CrossRefGoogle Scholar
  29. 29.
    Hopwood JJ, Muller V, Smithson A, Baggett N. A fluorometric assay using 4-methylumbelliferyl alpha-L-iduronide for the estimation of alpha-L-iduronidase activity and the detection of Hurler and Scheie syndromes. Clin Chim Acta. 1979;92(2):257–65.CrossRefGoogle Scholar
  30. 30.
    Santos E, Zarate J, Orive G, Hernández RM, Pedraz JL. Biomaterials in cell microencapsulation. Adv Exp Med Biol. 2010;670:5–21.CrossRefGoogle Scholar
  31. 31.
    Vériter S, Gianello P, Dufrane D. Bioengineered sites for islet cell transplantation. Curr Diab Rep. 2013;13:745–55.CrossRefGoogle Scholar
  32. 32.
    Cotugno G, Tessitore A, Capalbo A, Annunziata P, Strisciuglio C, Faella A, Aurilio M, Di Tommaso M, Russo F, Mancini A, De Leonibus E, Aloj L, Auricchio A. Different serum enzyme levels are required to rescue the various systemic features of the mucopolysaccharidoses. Hum Gene Ther. 2010;21(5):555–69.CrossRefGoogle Scholar
  33. 33.
    Wong SP, Argyros O, Harbottle RP. Sustained expression from DNA vectors. Adv Genet. 2015;89:113–52.Google Scholar
  34. 34.
    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;7:1482–91.CrossRefGoogle Scholar
  35. 35.
    Beck M. Therapy for lysosomal storage disorders. IUBMB Life. 2010;62:33–40.Google Scholar
  36. 36.
    Barsoum SC, Milgram W, Mackay W, Coblentz C, Delaney KH, Kwiecien JM, Kruth SA, Chang PL. Delivery of recombinant gene product to canine brain with the use of microencapsulation. J Lab Clin Med. 2003;142(6):399–413.CrossRefGoogle Scholar
  37. 37.
    Ciron C, Desmaris N, Colle M-A, Raoul S, Joussemet B, Vérot L, et al. Gene therapy of the brain in the dog model of Hurler’s syndrome. Ann Neurol. 2006;60:204–13.CrossRefGoogle Scholar
  38. 38.
    Di Domenico C, Villani G. Gene therapy for a mucopolysaccharidosis type I murine model with lentiviral-IDUA vector. Hum Gene Ther. 2005;90:81–90.CrossRefGoogle Scholar
  39. 39.
    Murua A, Castro M, de, Orive G. In vitro characterization and in vivo functionality of erythropoietin-secreting cells immobilized in alginate-poly-L-lysine-alginate microcapsules. Biomacromolecules. 2007;8:3302–7.CrossRefGoogle Scholar
  40. 40.
    Vériter S, Mergen J, Goebbels R-M, Aouassar N, Grégoire C, Jordan B, et al. In vivo selection of biocompatible alginates for islet encapsulation and subcutaneous transplantation. Tissue Eng Part A. 2010;16:1503–13.CrossRefGoogle Scholar
  41. 41.
    Tam SK, de Haan BJ, Faas MM, Hallé J-P, Yahia L, de Vos P. Adsorption of human immunoglobulin to implantable alginate-poly-L-lysine microcapsules: effect of microcapsule composition. J Biomed Mater Res A. 2009;89:609–15.CrossRefGoogle Scholar
  42. 42.
    Dusseault J, Tam SK, Ménard M, Polizu S, Jourdan G, Yahia L, et al. Evaluation of alginate purification methods: effect on polyphenol, endotoxin, and protein contamination. J Biomed Mater Res A. 2006;76:243–51.CrossRefGoogle Scholar
  43. 43.
    Rokstad AM, Lacík I, de Vos P, Strand BL. Advances in biocompatibility and physico-chemical characterization of microspheres for cell encapsulation. Adv Drug Deliv Rev. 2014;67–68:111–30.CrossRefGoogle Scholar
  44. 44.
    Murua A, Orive G, Hernández RM, Pedraz JL. Xenogeneic transplantation of erythropoietin-secreting cells immobilized in microcapsules using transiente immunosuppression. J Control Release. 2009;137(3):174–8.CrossRefGoogle Scholar
  45. 45.
    Acarregui A, Pedraz JL, Blanco FJ, Hernández RM, Orive G. Hydrogel-based scaffolds for enclosing encapsulated therapeutic cells. Biomacromolecules. 2013;14:322–30.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Valeska Lizzi Lagranha
    • 1
    • 2
  • Barbara Zambiasi Martinelli
    • 1
    • 3
  • Guilherme Baldo
    • 1
    • 2
    • 4
  • Giuseppe Ávila Testa
    • 1
  • Talita Giacomet de Carvalho
    • 1
    • 2
  • Roberto Giugliani
    • 1
    • 2
    • 3
  • Ursula Matte
    • 1
    • 2
  1. 1.Gene Therapy Center, Hospital de Clínicas de Porto AlegrePorto AlegreBrazil
  2. 2.Postgraduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do SulPorto AlegreBrazil
  3. 3.Postgraduate Program in Biochemistry, Universidade Federal do Rio Grande do SulPorto AlegreBrazil
  4. 4.Postgraduate Program in Physiology, Universidade Federal do Rio Grande do SulPorto AlegreBrazil

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