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Consistent Delivery of Adeno-Associated Virus via Lateral Tail-Vein Injection in Adult Mice
Published on: August 23, 2024
Characterization of a novel mucopolysaccharidosis type II mouse model and recombinant AAV2/8 vector-mediated gene
Sung-Chul Jung1, Eun-Sook Park, Eun Nam Choi
1Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul 158-710, Korea.
Abstract:
Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is an X-linked inherited disorder caused by a deficiency of the enzyme iduronate-2-sulfatase (IDS), which results in the lysosomal accumulation of glycosaminoglycans (GAG) such as dermatan and heparan sulfate. Here, we report the generation of IDS knockout mice, a model of human MPS II, and an analysis of the resulting phenotype. We also evaluated the effect of gene therapy with a pseudotyped, recombinant adeno-associated virus 2/8 vector encoding the human IDS gene (rAAV-hIDS) in IDS-deficient mice. IDS activity and GAG levels were measured in serum and tissues after therapy. Gene therapy completely restored IDS activity in plasma and tissue of the knockout mice. The rescued enzymatic activity completely cleared the accumulated GAGs in all the tissues analyzed. This model can be used to explore the therapeutic potential of IDS replacement and other strategies for the treatment of MPS II. Additionally, AAV2/8 vectors have promising future clinical applications for the treatment of patients with MPS II.
Insights
Gene therapy using AAV2/8 vectors restored enzyme activity and cleared GAGs in a mouse model of Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome. This study validates the mouse model for exploring MPS II treatments.
Area of Science:
- Genetics and Genetic Disorders
- Lysosomal Storage Diseases
- Gene Therapy
Background:
- Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is an X-linked inherited disorder.
- It is caused by a deficiency of iduronate-2-sulfatase (IDS) enzyme.
- This deficiency leads to the accumulation of glycosaminoglycans (GAGs) in lysosomes.
Purpose of the Study:
- To generate and characterize an IDS knockout mouse model for MPS II.
- To evaluate the efficacy of gene therapy using a recombinant adeno-associated virus (rAAV) vector in this model.
- To assess the potential of AAV2/8 vectors for clinical applications in MPS II treatment.
Main Methods:
- Generation of IDS knockout mice to model human MPS II.
- Administration of a pseudotyped, recombinant adeno-associated virus 2/8 vector encoding the human IDS gene (rAAV-hIDS).
- Measurement of IDS activity and GAG levels in serum and tissues post-therapy.
Main Results:
- Gene therapy completely restored IDS activity in plasma and tissues of IDS-deficient mice.
- The restored enzymatic activity effectively cleared accumulated GAGs from all analyzed tissues.
- The IDS knockout mouse model demonstrated a clear phenotype relevant to human MPS II.
Conclusions:
- The IDS knockout mouse is a valuable model for studying MPS II and evaluating therapeutic strategies.
- Gene therapy with rAAV-hIDS is highly effective in restoring enzyme function and clearing GAGs in this model.
- AAV2/8 vectors show significant promise for future clinical applications in treating MPS II patients.
