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Published on: August 10, 2018
Skeletal response to lentiviral mediated gene therapy in a mouse model of MPS VII
Carmen E Macsai1, Ainslie L K Derrick-Roberts, Xiaodan Ding
1Genetics and Molecular Pathology, SA Pathology (CYWHS Site), Adelaide, SA 5006, Australia.
Abstract:
Mucopolysaccharidosis VII (MPS VII) is an autosomal recessive, lysosomal storage disorder caused by β-glucuronidase (GUSB) deficiency, resulting in the accumulation of glycosaminoglycans (GAGs), in a variety of cell types. Severe, progressive skeletal pathology, termed dysostosis multiplex, is a prominent clinical feature of MPS VII. We have evaluated a gene therapy protocol for its efficacy in preventing the development and progression of bone pathology in MPS VII mice treated with a lentiviral vector at birth or at 7 weeks. Two weeks after injections, high levels of vector expression were observed in liver, spleen and bone marrow and to a lesser extent in kidney, lung and heart. Widespread clearance of GAG storage was observed in somatic tissues of both groups and some clearance of neuronal storage was observed in mice treated from birth. Micro-CT analysis demonstrated a significant decrease in vertebral and femoral bone mineral volume, trabecular number, bone surface density and cortical bone thickness in both treatment groups. Lumbar and femoral bone lengths were significantly decreased in untreated MPS VII mice, while growth plate heights were increased and these parameters did not change upon treatment. Small improvements in performance in the open field and rotarod behaviour tests were noted. Overall, systemic lentiviral-mediated gene therapy results in a measurable improvement in parameters of bone mass and architecture as well as biochemical and enzymatic correction. Conversely, growth plate chondrocytes were not responsive to treatment, as evidenced by the lack of improvement in vertebral and femoral bone length and growth plate height.
Insights
Gene therapy using lentiviral vectors shows promise for treating mucopolysaccharidosis VII (MPS VII) by improving bone health and reducing GAG storage. However, it did not restore growth plate function in MPS VII mice.
Area of Science:
- Genetics
- Biochemistry
- Medical Research
Background:
- Mucopolysaccharidosis VII (MPS VII) is a genetic lysosomal storage disorder due to beta-glucuronidase (GUSB) deficiency.
- Accumulation of glycosaminoglycans (GAGs) leads to severe skeletal pathology (dysostosis multiplex) in MPS VII.
Purpose of the Study:
- To evaluate the efficacy of lentiviral vector-mediated gene therapy in preventing bone pathology in MPS VII mice.
- To assess the impact of early- vs. late-stage treatment on disease progression.
Main Methods:
- MPS VII mice were treated at birth or 7 weeks with a lentiviral vector.
- Vector expression, GAG clearance, bone micro-architecture (Micro-CT), and behavioral tests were analyzed.
Main Results:
- Widespread GAG clearance in somatic and some neuronal tissues was observed.
- Gene therapy significantly improved bone mineral volume, density, and cortical thickness.
- Growth plate parameters (bone length, growth plate height) showed no improvement, indicating chondrocyte unresponsiveness.
Conclusions:
- Systemic lentiviral gene therapy offers measurable improvements in bone mass, architecture, and biochemical correction in MPS VII mice.
- Gene therapy did not restore growth plate chondrocyte function, highlighting limitations in addressing skeletal growth deficits.
