Systemic and central nervous system correction of lysosomal storage in mucopolysaccharidosis type VII mice

Mucopolysaccharidosis (MPS) type VII patients lack functional beta-glucuron idase, leading to systemic and central nervous system dysfunction, In this study we tested whether recombinant adenovirus that encodes beta-glucuronid ase (Ad beta gluc), delivered intravenously and into the brain parenchyma o f MPS type VII mice, could provide long-term transgene expression and corre ction of lysosomal distension. We also tested whether systemic treatment wi th the immunosuppressive anti-CD40 ligand antibody, MR-1, affected transgen e expression, We found substantial plasma beta-glucuronidase activity for o ver 9 weeks after gene transfer in the MR-1-treated group, with subsequent decline in activity corresponding to a delayed anti-beta-glucuronidase anti body response, At 16 weeks, near wild-type amounts of beta-glucuronidase ac tivity and striking reduction of lysosomal pathology were detected in liver s from mice that had received either MR-1 cotreatment or control antibody. In the lung and kidney, beta-glucuronidase activity was markedly higher for the MR-1-treated group. beta-Glucuronidase activity in the brain persisted independently of MR-1 treatment. Activity was intense in the injected hemi sphere and was also evident in the noninjected cortex and striatum, with dr amatic improvements in storage deposits in areas of both hemispheres, These results indicate that prolonged enzyme expression from transgenes delivere d to deficient liver and Brain can mediate pervasive correction and illustr ate the potential fur gene therapy of MPS and other lysosomal storage disea ses.