Abstract
Degenerative joint changes have been reported in human mucopolysaccharidosis VI (MPS VI) and are a prominent feature of feline MPS VI. Joint disease has proven refractory to intravenous enzyme replacement therapy (ERT) in the MPS VI cat because enzyme is unable to reach cells in cartilage. In this study, enzyme was infused directly into the intraarticular space to determine whether joint tissues are able to respond to replacement enzyme. Clearance of glycosaminoglycans from chondrocytes was observed at a dose of 10 μg recombinant human N-acetylgalactosamine-4-sulfatase (rh4S), but greater clearance was observed with higher doses. The chondrocytes at the articular surface were cleared preferentially. Lysosomal vacuolation in cruciate ligament and synovial cells also decreased upon addition of rh4S. One month after injection of rh4S, a slight reaccumulation of storage was observed at the surface of the joint, but extensive reaccumulation was observed 2 mo after injection. These results indicate that by bypassing the synovium using intraarticular ERT, significant reduction in storage material in joint tissues can be achieved. Localized ERT in the joint space provides a mechanism for delivering enzyme directly to the articular cartilage and a potential therapy for joint pathology in MPS VI.
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Abbreviations
- CS:
-
chondroitin sulphate
- DJD:
-
degenerative joint disease
- DS:
-
dermatan sulphate
- ERT:
-
enzyme replacement therapy
- GAG:
-
glycosaminoglycan
- IA INJ:
-
intraarticular injection
- MPS VI:
-
mucopolysaccharidosis VI
- rh4S:
-
recombinant human N-acetylgalactosamine-4-sulfatase
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Acknowledgements
The authors thank Prof. Mark Haskins, University of Pennsylvania, for the original heterozygous MPS VI cats; the animal care staff at the Institute of Medical and Veterinary Science for daily care of the cat colony; Ms. Lyn Waterhouse (Adelaide Microscopy, University of Adelaide) for TEM; and Dr. John W. Finnie (Veterinary Services Division, Institute of Medical and Veterinary Science) for regular histopathology assessments. We also thank Dr. Stuart Swiedler and Dr. Charles A. O'Neill, BioMarin Pharmaceutical Inc., for their regular support and input.
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This study was supported by grants from The National Health and Medical Research Council of Australia and BioMarin Pharmaceutical Inc.
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Auclair, D., Hein, L., Hopwood, J. et al. Intra-Articular Enzyme Administration for Joint Disease in Feline Mucopolysaccharidosis VI: Enzyme Dose and Interval. Pediatr Res 59, 538–543 (2006). https://doi.org/10.1203/01.pdr.0000203090.41012.a6
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DOI: https://doi.org/10.1203/01.pdr.0000203090.41012.a6
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