title: Intrathecal recombinant human 4-sulfatase reduces accumulation of glycosaminoglycans in dura of mucopolysaccharidosis VI cats.
abstract: BACKGROUND
  Mucopolysaccharidosis VI (MPS-VI) is caused by a deficiency in N-acetylgalactosamine-4-sulfatase activity, resulting in lysosomal accumulation of partially degraded glycosaminoglycans (GAGs). Compressive myelopathy in early-onset MPS-VI patients has been partly attributed to thickening of the dura mater following engorgement with GAG. In this study, we therefore tested whether the dural abnormalities could be prevented in a feline model of the disorder.
  
  
  RESULTS
  All intrathecal injections (IT-INJs) were well tolerated. MPS-VI cats treated with IT-INJ of recombinant human N-acetylgalactosamine-4-sulfatase (rhASB) exhibited reduced vacuolation in the dural fibroblasts, diminished levels of sulfated-N-acetylhexosamine (HNAc(+S)) in the cerebrospinal fluid (CSF) and no hind-limb paresis. Serum anti-rhASB antibodies remained low in MPS-VI cats treated with intravenous enzyme replacement therapy (IV-ERT) and increased slightly in normal cats treated with IT-INJ of rhASB alone. Anti-rhASB antibodies in CSF remained undetectable.
  
  
  CONCLUSIONS
  These data indicate that repeated IT-INJ of rhASB can safely prevent GAG storage in MPS-VI dura.
  
  
  METHODS
  Cats were assigned to three groups: (i) receiving weekly IV-ERT of rhASB from birth plus six monthly IT-INJs of rhASB from age 2 months; (ii) receiving six monthly IT-INJs of vehicle; or (iii) untreated. Additional normal cats received five fortnightly IT-INJs of rhASB or vehicle alone.
authors.affiliation: Lysosomal Diseases Research Unit, Research Centre of SA Pathology, North Adelaide, South Australia, Australia.
authors.forename: Dyane
authors.initials: D
authors.lastname: Auclair
authors.forename: John
authors.initials: J
authors.lastname: Finnie
authors.forename: Steven U
authors.initials: SU
authors.lastname: Walkley
authors.forename: Joleen
authors.initials: J
authors.lastname: White
authors.forename: Timothy
authors.initials: T
authors.lastname: Nielsen
authors.forename: Maria
authors.initials: M
authors.lastname: Fuller
authors.forename: Alphonsus
authors.initials: A
authors.lastname: Cheng
authors.forename: Charles A
authors.initials: CA
authors.lastname: O'Neill
authors.forename: John J
authors.initials: JJ
authors.lastname: Hopwood
mesh_terms: D000818:Animals; D002415:Cats; D004195:Disease Models, Animal; D004388:Dura Mater / Q000378:metabolism / Q000473:pathology*; D006025:Glycosaminoglycans / Q000378:metabolism*; D006801:Humans; D007278:Injections, Spinal; D009087:Mucopolysaccharidosis VI / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D020051:N-Acetylgalactosamine-4-Sulfatase / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D006025:Glycosaminoglycans; D011994:Recombinant Proteins; D020051:N-Acetylgalactosamine-4-Sulfatase