Skeletal response to lentiviral mediated gene therapy in a mouse model of MPS VII.

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.