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Journal of Inherited Metabolic Disease

, Volume 30, Issue 2, pp 227–238 | Cite as

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

  • A. Donsante
  • B. Levy
  • C. Vogler
  • M. S. Sands
Original Article

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.

Keywords

Enzyme Replacement Therapy Skeletal Dysplasia Lysosomal Storage Disease Alcian Blue Vector Copy Number 
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

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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Copyright information

© SSIEM and Springer 2007

Authors and Affiliations

  • A. Donsante
    • 1
  • B. Levy
    • 2
  • C. Vogler
    • 2
  • M. S. Sands
    • 1
    • 3
  1. 1.Department of Internal MedicineWashington University School of MedicineSt LouisUSA
  2. 2.Department of PathologySaint Louis University School of MedicineSt LouisUSA
  3. 3.Department of GeneticsWashington University School of MedicineSt LouisUSA

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