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1.
J Clin Invest ; 118(8): 2868-76, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18654665

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.


Subject(s)
Iduronidase/therapeutic use , Immune Tolerance , Lysosomal Storage Diseases/drug therapy , Mucopolysaccharidosis I/drug therapy , Animals , Azathioprine/pharmacology , Cyclosporine/pharmacology , Disease Models, Animal , Dogs , Dose-Response Relationship, Drug , Glycosaminoglycans/metabolism , Glycosaminoglycans/urine , Humans , Iduronidase/genetics , Iduronidase/metabolism , Iduronidase/pharmacology , Immunosuppressive Agents/pharmacology , Kidney/drug effects , Kidney/metabolism , Lysosomal Storage Diseases/pathology , Lysosomes/drug effects , Lysosomes/metabolism , Lysosomes/pathology , Mitral Valve/drug effects , Mitral Valve/metabolism , Mucopolysaccharidosis I/pathology , Recombinant Proteins/administration & dosage , Recombinant Proteins/metabolism , Recombinant Proteins/pharmacology , Recombinant Proteins/therapeutic use , Synovial Membrane/drug effects , Synovial Membrane/metabolism , Time Factors
2.
Mol Genet Metab ; 91(1): 61-8, 2007 May.
Article in English | MEDLINE | ID: mdl-17321776

ABSTRACT

Treatment of brain disease with recombinant proteins is difficult due to the blood-brain barrier. As an alternative to direct injections into the brain, we studied whether application of high concentrations of therapeutic enzymes via intrathecal (IT) injections could successfully drive uptake across the ependyma to treat brain disease. We studied IT enzyme replacement therapy with recombinant human iduronidase (rhIDU) in canine mucopolysaccharidosis I (MPS I, Hurler syndrome), a lysosomal storage disorder with brain and meningeal involvement. Monthly or quarterly IT treatment regimens with rhIDU achieved supranormal iduronidase enzyme levels in the brain, spinal cord, and spinal meninges. All regimens normalized total brain glycosaminoglycan (GAG) storage and reduced spinal meningeal GAG storage by 58-70%. The improvement in GAG storage levels persisted three months after the final IT dose. The successful use of enzyme therapy via the CSF represents a potentially useful approach for lysosomal storage disorders.


Subject(s)
Brain Diseases/drug therapy , Iduronidase/administration & dosage , Mucopolysaccharidosis I/drug therapy , Animals , Brain/drug effects , Brain/metabolism , Brain/pathology , Brain Diseases/pathology , Disease Models, Animal , Dogs , Dose-Response Relationship, Drug , Glycosaminoglycans/metabolism , Humans , Iduronidase/cerebrospinal fluid , Iduronidase/therapeutic use , Injections, Spinal , Meninges/drug effects , Meninges/metabolism , Meninges/pathology , Mucopolysaccharidosis I/pathology , Recombinant Proteins/administration & dosage , Recombinant Proteins/cerebrospinal fluid , Recombinant Proteins/therapeutic use , Spinal Cord/drug effects , Spinal Cord/metabolism , Spinal Cord/pathology , Tissue Distribution
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