Widespread biochemical correction of murine mucopolysaccharidosis type VII pathology by liver hydrodynamic plasmid delivery

Abstract

Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by a deficiency of the acid hydrolase b-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 b-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 b-glucuronidase cDNA, acquire the ability to produce the b-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.

Storage correction in cells of patients suffering from mucopolysaccharidoses types IIIA and VII after treatment with genistein and other isoflavones

“…New formulations of the molecules could also enable an increase in the circulating level and/or half-life of the compounds. Finally, the proposed substrate deprivation therapy could be used in combination with other therapeutic strategies restoring enzyme activity, such as nonviral liver-directed gene therapy (Richard et al 2009), which has demonstrated a significant biochemical and histological correction both in peripheral organs and in the CNS of MPS VII mice.…”

Innovative Therapeutic Approaches for Improving Patient Life Condition with a Neurological Lysosomal Disease

“…In spite of the results obtained on MPS VII mice by our group (Richard et al, 2009, the beneficial effect of gene transduction into the liver or other peripheral tissues is generally considered to be restricted to peripheral organs, as the secreted enzyme will not cross the blood brain barrier. Therefore, vector delivery systems have been developed for direct in vivo gene transfer into the CNS.…”

“…Non viral methods were also tested by our group to target the liver of MPS VII mice, using hydrodynamic injections of plasmid containing the beta-glucuronidase cDNA, leading to improvements in both peripheral and brain manifestations of MPS VII disease (Richard et al, 2009). The surprising biochemical correction observed in brain, while only the liver was producing the enzymes in this particular study, points to the possibility of the therapeutic enzymes crossing the blood-brain barrier (BBB) when continuously produced at the periphery.…”

Skeletal Muscle Metabolism in the Pathology and Treatment of Type 1 Diabetes

“…in muscle, greater secretion and therapeutic results have frequently been obtained after relatively similar transduction of other tissues more suited for these tasks, such as liver [204]. This suggests that ways to improve the processing and release of molecules from muscle are needed.…”