Abstract

Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease caused by β-glucuronidase (GUSB) deficiency. Intravenous injection of a retroviral vector expressing canine GUSB into neonatal MPS VII mice resulted in transduction of 6 to 35% of hepatocytes, which secreted GUSB into blood. Serum GUSB activity was stable for 6 months at 600 (low expression) to 10,000 (high expression) U/ml, and enzyme was modified appropriately with mannose 6-phosphate. The average serum GUSB activity (3531 U/ml) is the highest long-term expression reported for MPS VII mice after gene therapy. Secreted enzyme was taken up by other tissues, as the average enzyme activity was >13% of normal in somatic organs and 2% of normal in brain. Low expression markedly reduced histopathological evidence of lysosomal storage in liver, spleen, kidney, small intestine, neurons, and glial cells. High expression appeared to be more effective than low expression at reducing lysosomal storage in aorta, heart valves, thymus, bronchial epithelium, cornea, and retinal pigmented epithelium. Future experiments will determine if greater pathological improvements will consistently be observed in retrovirus-treated MPS VII mice with higher serum GUSB activity relative to animals with lower activity and if these result in clinical benefits.

Original languageEnglish
Pages (from-to)745-758
Number of pages14
JournalMolecular Therapy
Volume6
Issue number6
DOIs
StatePublished - Dec 1 2002

Keywords

  • Gene therapy
  • Glycosaminoglycans
  • Liver
  • Lysosomal storage disease
  • Mucopolysaccharidosis
  • Neonatal
  • Retroviral vector
  • β-glucuronidase

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