Immune tolerance improves the efficacy of enzyme replacement therapy in canine mucopolysaccharidosis I
Patricia Dickson, … , Merry Passage, Emil D. Kakkis
Patricia Dickson, … , Merry Passage, Emil D. Kakkis
Published July 24, 2008
Citation Information: J Clin Invest. 2008;118(8):2868-2876. https://doi.org/10.1172/JCI34676.
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Research Article

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 α-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 α-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

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Figure 4

Pathologic evidence that immune tolerance to ERT enhances reduction of lysosomal storage in treated dogs in kidney, synovium, and mitral valve.

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Pathologic evidence that immune tolerance to ERT enhances reduction of l...
Normal renal morphology from unaffected carriers is shown in the top row; arrows indicate epithelium lining distal cortical tubules. The untreated MPS I (Untr MPS I) dogs have swollen, GAG-laden cells lining distal cortical tubules and the synovium and within the mitral valve stroma. Interstitial “foam cells” (macrophages storing GAG) are common. Renal tubular cells from the nontolerant treated (Nontol 0.58 mg/kg) dogs have reduced storage, but GAG-laden interstitial macrophages persist. Synovial tissues contain modest amounts of cytoplasmic vacuolation in lining cells and reduced GAG-laden macrophages. Mitral valve storage is prominent. In tolerant dogs treated with 0.58 and 2 mg/kg, storage material is eliminated throughout renal cortical tissues. In the synovium, GAG-laden macrophages are absent and lining cell vacuolation is greatly reduced with low-dose treatment and entirely absent in the tolerant dogs treated at 2 mg/kg. Mitral valve storage is reduced in low dose–treated dogs, and cellular morphology resembles that of normal dogs in the tolerant animals treated with the higher, 2-mg/kg dose. Arrows indicate distal renal cortical tubules; proximal tubules are marked with asterisks. Arrowheads indicate accumulations of interstitial GAG-laden macrophages. All images show H&E staining. Original magnification, ×400.