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A novel mucopolysaccharidosis type II mouse model with an iduronate-2-sulfatase-P88L mutation
Ryuichi Mashima1, Mari Ohira2, Torayuki Okuyama2,3
1Department of Clinical Laboratory Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan. mashima-r@ncchd.go.jp.
Scientific Reports
|May 15, 2023
Summary
A novel mouse model for Mucopolysaccharidosis type II (MPS II) was developed, mimicking the human IDS-P86L mutation. This model shows impaired enzyme activity, elevated GAGs, and biomarker accumulation, aiding MPS II research.
Area of Science:
- Biochemistry
- Genetics
- Animal Models
Background:
- Mucopolysaccharidosis type II (MPS II) is a genetic lysosomal storage disorder.
- It involves glycosaminoglycan (GAG) accumulation, affecting the central nervous system (CNS) and skeletal structure.
- The severe form is often linked to the IDS-P86L mutation.
Purpose of the Study:
- To establish and characterize a novel mouse model for MPS II using an analogous mutation (Ids-P88L).
- To investigate the enzyme activity, GAG levels, and biomarker accumulation in this new model.
- To assess the potential of gene therapy for treating MPS II in this model.
Main Methods:
- Development of a novel Ids-P88L MPS II mouse model.
- Assessment of iduronate-2-sulfatase (IDS) enzyme activity in blood and various organs (liver, kidney, spleen, lung, heart).
- Quantification of GAG levels and the specific biomarker UA-HNAc(1S).
- Evaluation of nuclease-mediated genome correction for gene therapy.
Main Results:
- The Ids-P88L mouse model exhibited significantly impaired IDS enzyme activity and a reduced lifespan.
- Elevated GAG levels and accumulation of the UA-HNAc(1S) biomarker were observed, particularly in the liver.
- Gene therapy showed a marginal increase in IDS enzyme activity, suggesting potential for therapeutic assessment.
Conclusions:
- The novel Ids-P88L mouse model effectively recapitulates key features of human MPS II.
- This model serves as a valuable tool for studying MPS II pathogenesis and evaluating potential therapies.
- The findings support the investigation of gene correction strategies for MPS II.
