title: Intra-articular enzyme replacement therapy with rhIDUA is safe, well-tolerated, and reduces articular GAG storage in the canine model of mucopolysaccharidosis type I.
abstract: BACKGROUND
  Treatment with intravenous enzyme replacement therapy and hematopoietic stem cell transplantation for mucopolysaccharidosis (MPS) type I does not address joint disease, resulting in persistent orthopedic complications and impaired quality of life. A proof-of-concept study was conducted to determine the safety, tolerability, and efficacy of intra-articular recombinant human iduronidase (IA-rhIDUA) enzyme replacement therapy in the canine MPS I model.
  
  
  METHODS
  Four MPS I dogs underwent monthly rhIDUA injections (0.58 mg/joint) into the right elbow and knee for 6 months. Contralateral elbows and knees concurrently received normal saline. No intravenous rhIDUA therapy was administered. Monthly blood counts, chemistries, anti-rhIDUA antibody titers, and synovial fluid cell counts were measured. Lysosomal storage of synoviocytes and chondrocytes, synovial macrophages and plasma cells were scored at baseline and 1 month following the final injection.
  
  
  RESULTS
  All injections were well-tolerated without adverse reactions. One animal required prednisone for spinal cord compression. There were no clinically significant abnormalities in blood counts or chemistries. Circulating anti-rhIDUA antibody titers gradually increased in all dogs except the prednisone-treated dog; plasma cells, which were absent in all baseline synovial specimens, were predominantly found in synovium of rhIDUA-treated joints at study-end. Lysosomal storage in synoviocytes and chondrocytes following 6 months of IA-rhIDUA demonstrated significant reduction compared to tissues at baseline, and saline-treated tissues at study-end. Mean joint synovial GAG levels in IA-rhIDUA joints were 8.62 ± 5.86 μg/mg dry weight and 21.6 ± 10.4 μg/mg dry weight in control joints (60% reduction). Cartilage heparan sulfate was also reduced in the IA-rhIDUA joints (113 ± 39.5 ng/g wet weight) compared to saline-treated joints (142 ± 56.4 ng/g wet weight). Synovial macrophage infiltration, which was present in all joints at baseline, was abolished in rhIDUA-treated joints only.
  
  
  CONCLUSIONS
  Intra-articular rhIDUA is well-tolerated and safe in the canine MPS I animal model. Qualitative and quantitative assessments indicate that IA-rhIDUA successfully reduces tissue and cellular GAG storage in synovium and articular cartilage, including cartilage deep to the articular surface, and eliminates inflammatory macrophages from synovial tissue.
  
  
  CONCLUSIONS
  The MPS I canine IA-rhIDUA results suggest that clinical studies should be performed to determine if IA-rhIDUA is a viable approach to ameliorating refractory orthopedic disease in human MPS I.
authors.affiliation: Division of Metabolic Disorders, CHOC Children's, Orange, CA, USA. Electronic address: rawang@choc.org.
authors.forename: Raymond Y
authors.initials: RY
authors.lastname: Wang
authors.affiliation: Orthopedic Institute, CHOC Children's, Orange, CA, USA.
authors.forename: Afshin
authors.initials: A
authors.lastname: Aminian
authors.affiliation: Department of Biomedical and Diagnostic Sciences, University of Tennessee, Knoxville, TN, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: McEntee
authors.affiliation: Division of Medical Genetics, Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, CA, USA.
authors.forename: Shih-Hsin
authors.initials: SH
authors.lastname: Kan
authors.affiliation: Departments of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Calogera M
authors.initials: CM
authors.lastname: Simonaro
authors.affiliation: Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California-San Diego, La Jolla, CA, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Lamanna
authors.affiliation: Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California-San Diego, La Jolla, CA, USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Lawrence
authors.affiliation: Department of Animal Science, Iowa State University, Ames, IA, USA.
authors.forename: N Matthew
authors.initials: NM
authors.lastname: Ellinwood
authors.affiliation: Biological Resource Center, Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, CA, USA.
authors.forename: Catalina
authors.initials: C
authors.lastname: Guerra
authors.affiliation: Division of Medical Genetics, Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, CA, USA.
authors.forename: Steven Q
authors.initials: SQ
authors.lastname: Le
authors.affiliation: Division of Medical Genetics, Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, CA, USA.
authors.forename: Patricia I
authors.initials: PI
authors.lastname: Dickson
authors.affiliation: Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California-San Diego, La Jolla, CA, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Esko
mesh_terms: D000818:Animals; D000906:Antibodies / Q000097:blood; D002358:Cartilage, Articular / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D019902:Chondrocytes / Q000378:metabolism / Q000648:ultrastructure; D004195:Disease Models, Animal; D004285:Dogs; D056947:Enzyme Replacement Therapy; D006025:Glycosaminoglycans / Q000378:metabolism*; D006801:Humans; D007068:Iduronidase / Q000009:adverse effects* / Q000276:immunology / Q000627:therapeutic use*; D008059:Mucopolysaccharidosis I / Q000188:drug therapy* / Q000378:metabolism*; D010950:Plasma Cells / Q000378:metabolism; D011994:Recombinant Proteins / Q000627:therapeutic use; D013582:Synovial Fluid / Q000378:metabolism; D013583:Synovial Membrane / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000906:Antibodies; D006025:Glycosaminoglycans; D011994:Recombinant Proteins; D007068:Iduronidase
keywords: Canine; Lysosomal storage disorder; Model; Mucopolysaccharidosis; Orthopedic; Therapy