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Intrathecal recombinant human 4-sulfatase reduces accumulation of glycosaminoglycans in dura of mucopolysaccharidosis VI cats.

AbstractINTRODUCTION:
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.
DISCUSSION:
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.
AuthorsDyane Auclair, John Finnie, Steven U Walkley, Joleen White, Timothy Nielsen, Maria Fuller, Alphonsus Cheng, Charles A O'Neill, John J Hopwood
JournalPediatric research (Pediatr Res) Vol. 71 Issue 1 Pg. 39-45 (Jan 2012) ISSN: 1530-0447 [Electronic] United States
PMID22289849 (Publication Type: Journal Article)
Chemical References
  • Glycosaminoglycans
  • Recombinant Proteins
  • N-Acetylgalactosamine-4-Sulfatase
Topics
  • Animals
  • Cats
  • Disease Models, Animal
  • Dura Mater (metabolism, pathology)
  • Glycosaminoglycans (metabolism)
  • Humans
  • Injections, Spinal
  • Mucopolysaccharidosis VI (drug therapy, enzymology, pathology, physiopathology)
  • N-Acetylgalactosamine-4-Sulfatase (administration & dosage, genetics, therapeutic use)
  • Recombinant Proteins (administration & dosage, therapeutic use)
  • Treatment Outcome

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