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Clinical response to persistent, low-level β-glucuronidase expression in the murine model of mucopolysaccharidosis type VII

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by β-glucuronidase (GUSB) deficiency. This disease exhibits a broad spectrum of clinical signs including skeletal dysplasia, retinal degeneration, cognitive deficits and hearing impairment. Sustained, high-level expression of GUSB significantly improves the clinical course of the disease in the murine model of MPS VII. Low levels of enzyme expression (1–5% of normal) can significantly reduce the biochemical and histopathological manifestations of MPS VII. However, it has not been clear from previous studies whether persistent, low levels of circulating GUSB lead to significant improvements in the clinical presentation of this disease. We generated a rAAV2 vector that mediates persistent, low-level GUSB expression in the liver. Liver and serum levels of GUSB were maintained at ∼5% and ∼2.5% of normal, respectively, while other tissue ranged from background levels to 0.9%. This level of activity significantly reduced the secondary elevations of α-galactosidase and the levels of glycosaminoglycans in multiple tissues. Interestingly, this level of GUSB was also sufficient to reduce lysosomal storage in neurons in the brain. Although there were small but statistically significant improvements in retinal function, auditory function, skeletal dysplasia, and reproduction in rAAV-treated MPS VII mice, the clinical deficits were still profound and there was no improvement in lifespan. These data suggest that circulating levels of GUSB greater than 2.5% will be required to achieve substantial clinical improvements in MPS VII.

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Abbreviations

αGAL:

α-galactosidase

ABR:

auditory-evoked brainstem response

ERG:

electroretinogram

GAG:

glycosaminoglycan

GUSB:

β-glucuronidase

hAAT:

human α-1-antitrypsin

IU:

infectious units

LSD:

lysosomal storage disease

MPS VII:

mucopolysaccharidosis type VII

rAAV2:

recombinant adeno-associated virus serotype 2

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Authors and Affiliations

  1. Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri, USA

    A. Donsante & M. S. Sands

  2. Department of Pathology, Saint Louis University School of Medicine, St Louis, Missouri, USA

    B. Levy & C. Vogler

  3. Department of Genetics, Washington University School of Medicine, St Louis, Missouri, USA

    M. S. Sands

Authors
  1. A. Donsante
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  2. B. Levy
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  3. C. Vogler
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  4. M. S. Sands
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Corresponding author

Correspondence to M. S. Sands.

Additional information

Communicating editor: Ed Wraith

Competing interests: None declared

References to electronic databases: Mucopolysaccharidosis type VII, OMIM +253220; β-glucuronidase, EC 3.2.1.31.

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Donsante, A., Levy, B., Vogler, C. et al. Clinical response to persistent, low-level β-glucuronidase expression in the murine model of mucopolysaccharidosis type VII. J Inherit Metab Dis 30, 227–238 (2007). https://doi.org/10.1007/s10545-007-0483-4

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  • DOI: https://doi.org/10.1007/s10545-007-0483-4

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