Immune tolerance improves the efficacy of enzyme replacement therapy in canine mucopolysaccharidosis I.

Abstract

Mucopolysaccharidoses (MPSs) are lysosomal storage diseases caused by a deficit in the enzymes needed for glycosaminoglycan (GAG) degradation. Enzyme replacement therapy with recombinant human alpha-L-iduronidase successfully reduces lysosomal storage in canines and humans with iduronidase-deficient MPS I, but therapy usually also induces antibodies specific for the recombinant enzyme that could reduce its efficacy. To understand the potential impact of alpha-L-iduronidase-specific antibodies, we studied whether inducing antigen-specific immune tolerance to iduronidase could improve the effectiveness of recombinant iduronidase treatment in canines. A total of 24 canines with MPS I were either tolerized to iduronidase or left nontolerant. All canines received i.v. recombinant iduronidase at the FDA-approved human dose or a higher dose for 9-44 weeks. Nontolerized canines developed iduronidase-specific antibodies that proportionally reduced in vitro iduronidase uptake. Immune-tolerized canines achieved increased tissue enzyme levels at either dose in most nonreticular tissues and a greater reduction in tissue GAG levels, lysosomal pathology, and urinary GAG excretion. Tolerized MPS I dogs treated with the higher dose received some further benefit in the reduction of GAGs in tissues, urine, and the heart valve. Therefore, immune tolerance to iduronidase improved the efficacy of enzyme replacement therapy with recombinant iduronidase in canine MPS I and could potentially improve outcomes in patients with MPS I and other lysosomal storage diseases.

• Authors: Patricia Dickson, Maryn Peinovich, Michael McEntee, Thomas Lester, Steven Le, Aimee Krieger, Hayden Manuel, Catherine Jabagat, Merry Passage, Emil D Kakkis
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 118 Issue 8 Pg. 2868-76 (Aug 2008) ISSN: 0021-9738 [Print] United States
• PMID: 18654665 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Glycosaminoglycans
• Immunosuppressive Agents
• Recombinant Proteins
• Cyclosporine
• Iduronidase
• Azathioprine

Topics

• Animals
• Azathioprine (pharmacology)
• Cyclosporine (pharmacology)
• Disease Models, Animal
• Dogs
• Dose-Response Relationship, Drug
• Glycosaminoglycans (metabolism, urine)
• Humans
• Iduronidase (genetics, metabolism, pharmacology, therapeutic use)
• Immune Tolerance
• Immunosuppressive Agents (pharmacology)
• Kidney (drug effects, metabolism)
• Lysosomal Storage Diseases (drug therapy, pathology)
• Lysosomes (drug effects, metabolism, pathology)
• Mitral Valve (drug effects, metabolism)
• Mucopolysaccharidosis I (drug therapy, pathology)
• Recombinant Proteins (administration & dosage, metabolism, pharmacology, therapeutic use)
• Synovial Membrane (drug effects, metabolism)
• Time Factors