Abstract
Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by a deficiency of the acid hydrolase β-glucuronidase. MPS VII mice develop progressive lysosomal accumulation of glycosaminoglycans (GAGs) within multiple organs, including the brain. Using this animal model, we compared two plasmid gene administration techniques: muscle electrotransfer and liver-directed transfer using hydrodynamic injection. We have evaluated both the expression kinetics and the biodistribution of β-glucuronidase activity after gene transfer, as well as the correction of biochemical abnormalities in various organs. This study shows that MPS VII mice treated with a plasmid-bearing mouse β-glucuronidase cDNA, acquire the ability to produce the β-glucuronidase enzyme for an extended period of time. The liver seemed to be more appropriate than the muscle as a target organ to enable enzyme secretion into the systemic circulation. A beneficial effect on the MPS VII pathology was also observed, as liver-directed gene transfer led to the correction of secondary enzymatic elevations and to the reduction of GAGs storage in peripheral tissues and brain, as well as to histological correction in many tissues. This work is one of the first examples showing that non-viral plasmid DNA delivery can lead to improvements in both peripheral and brain manifestations of MPS VII disease. It confirms the potential of non-viral systemic gene transfer strategy in neurological lysosomal disorders.
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Acknowledgements
We thank Dr B Soper for generously providing the gusmps/gusmps mice, as well as Dr J Grubb for kindly providing the murine β-glucuronidase protein. We thank also Dr J-M Caillaud (Biodoxis, Romainville, France) for his support in performing bright field microscopy histological analyses of tissues. This work was supported by European ‘MOLEDA’ STREP and European ‘CLINIGENE’ Network of Excellence. MR and AA received sponsorship from MOLEDA and CLINIGENE, respectively.
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Richard, M., Arfi, A., Seguin, J. et al. Widespread biochemical correction of murine mucopolysaccharidosis type VII pathology by liver hydrodynamic plasmid delivery. Gene Ther 16, 746–756 (2009). https://doi.org/10.1038/gt.2009.36
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DOI: https://doi.org/10.1038/gt.2009.36
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