Murine mucopolysaccharidosis type VII. Characterization of a mouse with beta-glucuronidase deficiency.

Abstract

We have characterized a new mutant mouse that

Treatment of lysosomal storage disease in MPS VII mice using a recombinant adeno-associated virus

“…4 Nearly null or NN mice have the genotype Gus am/am and do not display storage disease symptoms in spite of their low levels of GUS enzyme. A comparison of GUS activities among normal (Gus +/+ ), MPS and NN mice is shown in Table 1.…”

“…This in turn results in animals that have distorted facial features, defects in skeletal development, dwarfism, reduced learning capacity, and early death at approximately 5 months of age. 4,6 Another useful mutation in mice is the 'nearly null' GUS mutation, which was developed by V Chapman at Roswell Park Cancer Institute. These mice have only 1-3% of normal GUS activity yet do not display any overt MPS phenotypes.…”

Prevention of systemic clinical disease in MPS VII mice following AAV-mediated neonatal gene transfer

“…Although MPS VII is rare in humans, the disease shares many symptoms with more common lysosomal storage disorders such as Hunter's and Hurler's, and several authentic animal models of MPS VII have been characterized. [2][3][4] Therefore, MPS VII has been used as a model system for lysosomal disease in general. A murine model of MPS VII has been described that has no detectable GUSB activity and is caused by a single base pair deletion in exon 10 of the murine gene.…”

“…A murine model of MPS VII has been described that has no detectable GUSB activity and is caused by a single base pair deletion in exon 10 of the murine gene. 3,5 The MPS VII mouse model recapitulates many of the symptoms seen in human patients, and has been widely used in the evaluation of therapeutic strategies for lysosomal storage diseases.…”

Gene therapy in the CNS

“…A mouse model of mucopolysaccharidosis type VII (MPS VII) resulting from a mutation in the gene for beta-glucuronidase (GUS) has been the most commonly used model to study different gene therapy approaches to lysosomal disorders affecting the brain. 224 Restoration of GUS activity in the brain was attempted by directly injecting the HSV or Ad vectors encoding GUS into the cornea or striatum, respectively. 225,226 In both treatments the expression of the enzyme was limited to a few specific neuronal areas, although the intrastriatal injection resulted in the widespread presence of enzyme activity within the neocortex.…”