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Published on: June 8, 2014
Long circulating enzyme replacement therapy rescues bone pathology in mucopolysaccharidosis VII murine model
Daniel J Rowan1, Shunji Tomatsu, Jeffrey H Grubb
1School of Medicine, Saint Louis University, St. Louis, MO, USA.
Abstract:
Mucopolysaccharidosis (MPS) type VII is a lysosomal storage disease caused by deficiency of the lysosomal enzyme β-glucuronidase (GUS), leading to accumulation of glycosaminoglycans (GAGs). Enzyme replacement therapy (ERT) effectively clears GAG storage in the viscera. Recent studies showed that a chemically modified form of GUS (PerT-GUS), which escaped clearance by mannose 6-phosphate and mannose receptors and showed prolonged circulation, reduced CNS storage more effectively than native GUS. Clearance of storage in bone has been limited due to the avascularity of the growth plate. To evaluate the effectiveness of long-circulating PerT-GUS in reducing the skeletal pathology, we treated MPS VII mice for 12 weeks beginning at 5 weeks of age with PerT-GUS or native GUS and used micro-CT, radiographs, and quantitative histopathological analysis for assessment of bones. Micro-CT findings showed PerT-GUS treated mice had a significantly lower BMD. Histopathological analysis also showed reduced storage material and a more organized growth plate in PerT-GUS treated mice compared with native GUS treated mice. Long term treatment with PerT-GUS from birth up to 57 weeks also significantly improved bone lesions demonstrated by micro-CT, radiographs and quantitative histopathological assay. In conclusion, long-circulating PerT-GUS provides a significant impact to rescue of bone lesions and CNS involvement.
Insights
Modified beta-glucuronidase (PerT-GUS) enzyme replacement therapy significantly improved bone lesions in Mucopolysaccharidosis type VII mice. This long-circulating enzyme effectively reduced skeletal pathology and central nervous system storage.
Area of Science:
- Biochemistry
- Genetics
- Medical Science
Background:
- Mucopolysaccharidosis (MPS) type VII is a genetic lysosomal storage disease due to beta-glucuronidase (GUS) deficiency.
- This deficiency leads to the accumulation of glycosaminoglycans (GAGs), causing widespread tissue damage.
- Current enzyme replacement therapy (ERT) using native GUS has limitations, particularly in treating skeletal and central nervous system (CNS) pathology.
Purpose of the Study:
- To evaluate the efficacy of a chemically modified, long-circulating form of GUS (PerT-GUS) in ameliorating skeletal pathology in MPS type VII mice.
- To compare the effectiveness of PerT-GUS with native GUS in treating bone lesions.
- To assess the impact of PerT-GUS on CNS storage in MPS VII models.
Main Methods:
- MPS VII mice were treated with PerT-GUS or native GUS for 12 weeks, starting at 5 weeks of age.
- Skeletal assessments were performed using micro-computed tomography (micro-CT), radiographs, and quantitative histopathology.
- Long-term treatment up to 57 weeks was also evaluated for its effects on bone lesions.
Main Results:
- PerT-GUS treatment resulted in significantly improved bone mineral density (BMD) and reduced GAG storage in the growth plate compared to native GUS.
- Histopathological analysis revealed a more organized growth plate structure in PerT-GUS treated mice.
- Long-term PerT-GUS administration significantly improved bone lesions, as evidenced by micro-CT, radiographs, and histopathology.
Conclusions:
- Long-circulating PerT-GUS demonstrates significant therapeutic potential for rescuing bone lesions in MPS type VII.
- PerT-GUS offers an improved strategy for addressing skeletal and CNS manifestations of MPS type VII compared to native GUS.
- This modified enzyme may represent a more effective ERT approach for lysosomal storage diseases with skeletal involvement.
