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Early initiation of enzyme replacement therapy improves metabolic correction in the brain tissue of aspartylglycosaminuria mice

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Aspartylglycosaminuria (AGU) is a lysosomal storage disease caused by deficient activity of glycosylasparaginase (AGA), and characterized by motor and mental retardation. Enzyme replacement therapy (ERT) in adult AGU mice with AGA removes the accumulating substance aspartylglucosamine from and reverses pathology in many somatic tissues, but has only limited efficacy in the brain tissue of the animals. In the current work, ERT of AGU mice was initiated at the age of 1 week with three different dosage schedules of recombinant glycosylasparaginase. The animals received either 3.4 U of AGA/kg every second day for 2 weeks (Group 1), 1.7 U/kg every second day for 9 days followed by an enzyme injection once a week for 4 weeks (Group 2) or 17 U/kg at the age of 7 and 9 days (Group 3). In the Group 1 and Group 3 mice, ERT reduced the amount of aspartylglucosamine by 34 and 41% in the brain tissue, respectively. No therapeutic effect was observed in the brain tissue of Group 2 mice. As in the case of adult AGU mice, the AGA therapy was much more effective in the somatic tissues than in the brain tissue of the newborn AGU mice. The combined evidence demonstrates that a high dose ERT with AGA in newborn AGU mice is up to twofold more effective in reducing the amount of the accumulated storage material from the brain tissue than ERT in adult AGU animals, indicating the importance of early detection and treatment of the disease.

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Abbreviations

AGA:

Glycosylasparaginase

AGU:

Aspartylglycosaminuria

BBB:

Blood–brain barrier

GlcNAc-Asn:

Aspartylglucosamine

CNS:

Central nervous system

ERT:

Enzyme replacement therapy

M-6-P:

Mannose-6-phosphate

MSP:

Mucopolysaccharidosis

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Acknowledgements

This work was financially supported by grants from The Sigrid Juselius Foundation (I.M.), the Pediatric Research Foundation (Ulla Hjelt Fund) (I.M.), and Kuopio University Hospital (EVO grant #5100).

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Authors and Affiliations

  1. Eastern Finland Laboratory Centre, Kuopio, Finland

    Ulla Dunder

  2. Clinical Chemistry, University of Kuopio, Kuopio, Finland

    Ulla Dunder, Pirjo Valtonen & Eira Kelo

  3. Department of Clinical Chemistry and Hematology, University of Turku and TUCH Laboratories, Kiinamyllynkatu 4-8, 20520, Turku, Finland

    Ilkka Mononen

Authors
  1. Ulla Dunder
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  2. Pirjo Valtonen
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  3. Eira Kelo
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  4. Ilkka Mononen
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Corresponding author

Correspondence to Ilkka Mononen.

Additional information

Communicated by: Olaf Bodamer

References to electronic databases: Aspartylglucosaminuria: OMIM #208400; Glycosylasparaginase: EC 3.5.1.26

Competing interests: None declared.

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Dunder, U., Valtonen, P., Kelo, E. et al. Early initiation of enzyme replacement therapy improves metabolic correction in the brain tissue of aspartylglycosaminuria mice. J Inherit Metab Dis 33, 611–617 (2010). https://doi.org/10.1007/s10545-010-9158-7

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  • DOI: https://doi.org/10.1007/s10545-010-9158-7

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