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Mucopolysaccharidosis type VII in the developing mouse fetus
1Department of Pathobiology and Center for Comparative Medical Genetics, School of Veterinary Medicine, University of Pennsylvania, Philadelphia 19104, USA.
Abstract:
Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by a deficiency of beta-glucuronidase (1). MPS VII is a fatal, progressive degenerative disorder, and a number of patients die of hydrops fetalis. Thus an approach to treating this disease may be by transplantation or gene therapy in utero. A mouse model of MPS VII has been studied extensively but the disease in affected fetal mice has not been characterized, which is essential for evaluation of therapeutic efficacy. Fetal and newborn mice affected with MPS VII were examined for lysosomal enzyme activities and for the presence of typical storage lesions in comparison to normal and carrier littermates. No beta-glucuronidase enzymatic activity was detected in any of the tissues of affected mice, indicating that transplacental transfer of beta-glucuronidase from the dam did not occur. Lesions were not detected in affected fetuses of 13.5 d gestational age on light or electron microscopy. Vacuolation in cells, typical of lysosomal accumulation of substrate, was first seen in a small number of cells of the reticulo-endothelial system in 15.5 d gestational age livers and in 18.5 d gestational age brains. Storage lesions were not seen consistently in endothelial and Kupffer cells of fetal livers until 18.5 d gestational age and in brains until birth. The results suggest that treatment of affected mice performed at 13.5 d gestational age may be effective in forestalling disease manifestations.
Insights
Mucopolysaccharidosis type VII (MPS VII), a severe lysosomal storage disease, shows no beta-glucuronidase activity in affected fetal mice. Early prenatal treatment may prevent disease onset in this MPS VII mouse model.
Area of Science:
- Biochemistry
- Genetics
- Developmental Biology
Background:
- Mucopolysaccharidosis type VII (MPS VII) is a fatal lysosomal storage disease due to beta-glucuronidase deficiency.
- Hydrops fetalis is a common cause of mortality in MPS VII patients.
- In utero transplantation or gene therapy are potential treatment strategies for MPS VII.
Purpose of the Study:
- Characterize the fetal disease progression in a mouse model of MPS VII.
- Determine the earliest onset of storage lesions in MPS VII fetal mice.
- Establish an optimal window for potential in utero therapeutic interventions.
Main Methods:
- Assessed beta-glucuronidase enzyme activity in tissues of affected and control fetal mice.
- Utilized light and electron microscopy to identify storage lesions in fetal tissues.
- Examined MPS VII mice at various gestational ages (13.5, 15.5, 18.5 days) and at birth.
Main Results:
- No detectable beta-glucuronidase activity was found in MPS VII fetal mice, confirming lack of transplacental enzyme transfer.
- Storage lesions were absent at 13.5 days gestation but appeared in the reticulo-endothelial system by 15.5 days gestation.
- Consistent storage lesions were observed in fetal livers by 18.5 days gestation and in brains at birth.
Conclusions:
- Fetal MPS VII mouse models exhibit a progressive development of storage lesions starting mid-gestation.
- Early prenatal intervention, potentially at 13.5 days gestation, could be effective in preventing disease manifestations.
- This study provides crucial data for evaluating the efficacy of in utero therapies for MPS VII.