title: Intrathecal enzyme replacement therapy: successful treatment of brain disease via the cerebrospinal fluid.
abstract: Treatment of brain disease with recombinant proteins is difficult due to the blood-brain barrier. As an alternative to direct injections into the brain, we studied whether application of high concentrations of therapeutic enzymes via intrathecal (IT) injections could successfully drive uptake across the ependyma to treat brain disease. We studied IT enzyme replacement therapy with recombinant human iduronidase (rhIDU) in canine mucopolysaccharidosis I (MPS I, Hurler syndrome), a lysosomal storage disorder with brain and meningeal involvement. Monthly or quarterly IT treatment regimens with rhIDU achieved supranormal iduronidase enzyme levels in the brain, spinal cord, and spinal meninges. All regimens normalized total brain glycosaminoglycan (GAG) storage and reduced spinal meningeal GAG storage by 58-70%. The improvement in GAG storage levels persisted three months after the final IT dose. The successful use of enzyme therapy via the CSF represents a potentially useful approach for lysosomal storage disorders.
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, LA Biomed at Harbor-UCLA, Torrance, CA 90502, USA. pdickson@ucla.edu
authors.forename: Patricia
authors.initials: P
authors.lastname: Dickson
authors.forename: Michael
authors.initials: M
authors.lastname: McEntee
authors.forename: Carole
authors.initials: C
authors.lastname: Vogler
authors.forename: Steven
authors.initials: S
authors.lastname: Le
authors.forename: Beth
authors.initials: B
authors.lastname: Levy
authors.forename: Maryn
authors.initials: M
authors.lastname: Peinovich
authors.forename: Stephen
authors.initials: S
authors.lastname: Hanson
authors.forename: Merry
authors.initials: M
authors.lastname: Passage
authors.forename: Emil
authors.initials: E
authors.lastname: Kakkis
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001927:Brain Diseases / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D007068:Iduronidase / Q000008:administration & dosage* / Q000134:cerebrospinal fluid / Q000627:therapeutic use; D007278:Injections, Spinal; D008578:Meninges / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008059:Mucopolysaccharidosis I / Q000188:drug therapy* / Q000473:pathology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000134:cerebrospinal fluid / Q000627:therapeutic use; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014018:Tissue Distribution
chemical_list: D006025:Glycosaminoglycans; D011994:Recombinant Proteins; D007068:Iduronidase