Active site mutant transgene confers tolerance to human beta-glucuronidasewithout affecting the phenotype of MPS VII mice

Mucopolysaccharidosis type VII (MPS VII; Sly syndrome) is an autosomal rece ssive lysosomal storage disorder due to an inherited deficiency of beta -gl ucuronidase. A naturally occurring mouse model for this disease was discove red at The Jackson Laboratory and shown to be due to homozygosity for a 1-b p deletion in exon 10 of the gus gene. The murine model MPS VII (gus(mps/mp s)) has been very well characterized and used extensively to evaluate exper imental strategies for lysosomal storage diseases, including bone marrow tr ansplantation, enzyme replacement therapy, and gene therapy. To enhance the value of this model for enzyme and gene therapy, we produced a transgenic mouse expressing the human beta -glucuronidase cDNA with an amino acid subs titution at the active site nucleophile (E540A) and bred it onto the MPS VI I (gus(mps/mps)) background. We demonstrate here that the mutant mice beari ng the active site mutant human transgene retain the clinical, morphologica l, biochemical, and histopathological characteristics of the original MPS V II (gus(mps/mps)) mouse. However, they are now tolerant to immune challenge with human beta -glucuronidase. This "tolerant MPS VII mouse model" should be useful for preclinical trials evaluating the effectiveness of enzyme an d/or gene therapy with the human gene products likely to be administered to human patients with MPS VII.