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Correction of murine mucopolysaccharidosis VII by a human beta-glucuronidase transgene
J W Kyle1, E H Birkenmeier, B Gwynn
1Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, MO 63104.
Abstract:
We recently described a murine model for mucopolysaccharidosis VII in mice that have an inherited deficiency of beta-glucuronidase (beta-D-glucuronoside glucuronosohydrolase, EC 3.2.1.31). Affected mice, of genotype gusmps/gusmps, present clinical manifestations similar to those of humans with mucopolysaccharidosis VII (Sly syndrome) and are shown here to have secondary elevations of other lysosomal enzymes. The mucopolysaccharidosis VII phenotype in both species includes dwarfism, skeletal deformities, and premature death. Lysosome storage is visualized within enlarge vesicles and correlates biochemically with accumulation of undegraded and partially degraded glycosaminoglycans. In this report we describe the consequences of introducing the human beta-glucuronidase gene, GUSB, into gusmps/gusmps mice that produce virtually no murine beta-glucuronidase. Transgenic mice homozygous for the mucopolysaccharidosis VII mutation expressed high levels of human beta-glucuronidase activity in all tissues examined and were phenotypically normal. Biochemically, both the intralysosomal storage of glycosaminoglycans and the secondary elevation of other acid hydrolases were corrected. These findings demonstrate that the GUSB transgene is expressed in gusmps/gusmps mice and that human beta-glucuronidase corrects the murine mucopolysaccharidosis storage disease.
Insights
Gene therapy using the human beta-glucuronidase (GUSB) gene successfully corrected mucopolysaccharidosis VII in mice. This breakthrough offers hope for treating this rare genetic disorder by restoring enzyme function and alleviating disease symptoms.
Area of Science:
- Genetics
- Lysosomal Storage Diseases
- Biochemistry
Background:
- Mucopolysaccharidosis VII (Sly syndrome) is a rare genetic disorder caused by beta-glucuronidase deficiency.
- Affected individuals and a murine model exhibit dwarfism, skeletal deformities, premature death, and lysosomal storage of glycosaminoglycans.
- Secondary elevations of other lysosomal enzymes are observed in the murine model.
Purpose of the Study:
- To investigate the therapeutic potential of introducing the human beta-glucuronidase (GUSB) gene into a murine model of mucopolysaccharidosis VII.
- To assess the expression and efficacy of the human GUSB transgene in correcting the disease phenotype and biochemical abnormalities.
Main Methods:
- Generation of transgenic mice by introducing the human GUSB gene into mice with a genetic deficiency in beta-glucuronidase (gusmps/gusmps genotype).
- Analysis of beta-glucuronidase activity in various tissues of the transgenic mice.
- Biochemical assessment of glycosaminoglycan accumulation and secondary lysosomal enzyme levels.
- Evaluation of phenotypic characteristics, including growth and survival.
Main Results:
- Transgenic mice expressed high levels of human beta-glucuronidase activity across all examined tissues.
- The gusmps/gusmps mice carrying the GUSB transgene were phenotypically normal, showing correction of dwarfism and skeletal deformities.
- Intralysosomal storage of glycosaminoglycans was normalized, and secondary elevations of other acid hydrolases were corrected.
- The GUSB transgene was effectively expressed and functional in the murine model.
Conclusions:
- Introduction of the human GUSB gene successfully corrects the biochemical and phenotypic manifestations of mucopolysaccharidosis VII in mice.
- Gene augmentation therapy with human beta-glucuronidase is a viable strategy for treating this lysosomal storage disease.
- These findings support the potential translation of this gene therapy approach to human patients with Sly syndrome.