title: Overcoming the blood-brain barrier with high-dose enzyme replacement therapy in murine mucopolysaccharidosis VII.
abstract: Enzyme replacement therapy (ERT) effectively reverses storage in several lysosomal storage diseases. However, improvement in brain is limited by the blood-brain barrier except in the newborn period. In this study, we asked whether this barrier could be overcome by higher doses of enzyme than are used in conventional trials. We measured the distribution of recombinant human beta-glucuronidase (hGUS) and reduction in storage by weekly doses of 0.3-40 mg/kg administered i.v. over 1-13 weeks to mucopolysaccharidosis type VII mice immunotolerant to recombinant hGUS. Mice given up to 5 mg/kg enzyme weekly over 3 weeks had moderate reduction in meningeal storage but no change in neo-cortical neurons. Mice given 20-40 mg/kg three times over 1 week showed no reduction in storage in any area of the CNS except the meninges. In contrast, mice receiving 4 mg/kg per week for 13 weeks showed clearance not only in meninges but also in parietal neocortical and hippocampal neurons and glia. Mice given 20 mg/kg once weekly for 4 weeks also had decreased neuronal, glial, and meningeal storage and averaged 2.5% of wild-type hGUS activity in brain. These results indicate that therapeutic enzyme can be delivered across the blood-brain barrier in the adult mucopolysaccharidosis type VII mouse if administered at higher doses than are used in conventional ERT trials and if the larger dose of enzyme is administered over a sufficient period. These results may have important implications for ERT for lysosomal storage diseases with CNS involvement.
authors.affiliation: Department of Pathology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
authors.forename: Carole
authors.initials: C
authors.lastname: Vogler
authors.forename: Beth
authors.initials: B
authors.lastname: Levy
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Grubb
authors.forename: Nancy
authors.initials: N
authors.lastname: Galvin
authors.forename: Yun
authors.initials: Y
authors.lastname: Tan
authors.forename: Emil
authors.initials: E
authors.lastname: Kakkis
authors.forename: Nadine
authors.initials: N
authors.lastname: Pavloff
authors.forename: William S
authors.initials: WS
authors.lastname: Sly
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005966:Glucuronidase / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006652:Histological Techniques; D006801:Humans; D008578:Meninges / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D016538:Mucopolysaccharidosis VII / Q000188:drug therapy* / Q000201:enzymology*; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology
chemical_list: D005966:Glucuronidase