Clinical response to persistent, low-level β-glucuronidase expression in the murine model of mucopolysaccharidosis type VII
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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.
KeywordsEnzyme Replacement Therapy Skeletal Dysplasia Lysosomal Storage Disease Alcian Blue Vector Copy Number
auditory-evoked brainstem response
lysosomal storage disease
- MPS VII
mucopolysaccharidosis type VII
recombinant adeno-associated virus serotype 2
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- Daly TM, Okuyama T, Vogler C, Haskins ME, Muzyczka N, Sands MS (1999b) Neonatal intramuscular injection with recombinant adeno-associated virus results in prolonged beta-glucuronidase expression in situ and correction of liver pathology in mucopolysaccharidosis type VII mice. Hum Gene Ther 10(1): 85–94.CrossRefGoogle Scholar
- Neufeld EF, Muenzer J (2001) The mucopolysaccharisdoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds; Childs B, Kinzler KW, Vogelstein B, assoc, eds. The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw-Hill, 3421–3452.Google Scholar
- Vogler C, Sands MS, Levy B, Galvin N, Birkenmeier EH, Sly WS (1996) Enzyme replacement with recombinant beta-glucuronidase in murine mucopolysaccharidosis type VII: impact of therapy during the first six weeks of life on subsequent lysosomal storage, growth, and survival. Pediatr Res 39(6): 1050–1054.PubMedGoogle Scholar
- Vogler C, Levy B, Galvin N, Lessard M, Soper B, Barker J (2005b) Early onset of lysosomal storage disease in a murine model of mucopolysaccharidosis type VII: undegraded substrate accumulates in many tissues in the fetus and very young MPS VII mouse. Pediatr Dev Pathol 8(4): 453–462.CrossRefGoogle Scholar