Format

Send to

Choose Destination
See comment in PubMed Commons below
Mol Genet Metab. 2014 Aug;112(4):286-93. doi: 10.1016/j.ymgme.2014.05.015. Epub 2014 Jun 6.

Intra-articular enzyme replacement therapy with rhIDUA is safe, well-tolerated, and reduces articular GAG storage in the canine model of mucopolysaccharidosis type I.

Author information

1
Division of Metabolic Disorders, CHOC Children's, Orange, CA, USA. Electronic address: rawang@choc.org.
2
Orthopedic Institute, CHOC Children's, Orange, CA, USA.
3
Department of Biomedical and Diagnostic Sciences, University of Tennessee, Knoxville, TN, USA.
4
Division of Medical Genetics, Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, CA, USA.
5
Departments of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
6
Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California-San Diego, La Jolla, CA, USA.
7
Department of Animal Science, Iowa State University, Ames, IA, USA.
8
Biological Resource Center, Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, CA, USA.

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.

CLINICAL RELEVANCE:

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.

KEYWORDS:

Canine; Lysosomal storage disorder; Model; Mucopolysaccharidosis; Orthopedic; Therapy

PMID:
24951454
PMCID:
PMC4122635
DOI:
10.1016/j.ymgme.2014.05.015
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Support Center