Replacing the enzyme alpha-L-iduronidase at birth ameliorates symptoms in the brain and periphery of dogs with mucopolysaccharidosis type I

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease caused by loss of activity of α-l-iduronidase and attendant accumulation of the glycosaminoglycans dermatan sulfate and heparan sulfate. Current treatments are suboptimal and do not address residual disease including corneal cloudin...

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Bibliographic Details
Published in:	Science translational medicine Vol. 2; no. 60; p. 60ra89
Main Authors:	Dierenfeld, Ashley D, McEntee, Michael F, Vogler, Carole A, Vite, Charles H, Chen, Agnes H, Passage, Merry, Le, Steven, Shah, Sahil, Jens, Jackie K, Snella, Elizabeth M, Kline, Karen L, Parkes, Jennifer D, Ware, Wendy A, Moran, Lori E, Fales-Williams, Amanda J, Wengert, Jane A, Whitley, R David, Betts, Daniel M, Boal, Amy M, Riedesel, Elizabeth A, Gross, William, Ellinwood, N Matthew, Dickson, Patricia I
Format:	Journal Article
Language:	English
Published:	United States 01-12-2010
Subjects:	Animals Animals, Newborn Bone and Bones - pathology Brain - metabolism Brain - pathology Dogs Enzyme Therapy Glycosaminoglycans - metabolism Humans Iduronidase - administration & dosage Iduronidase - genetics Iduronidase - therapeutic use Joints - pathology Lysosomes - metabolism Mucopolysaccharidosis I - pathology Mucopolysaccharidosis I - physiopathology Mucopolysaccharidosis I - therapy Tissue Distribution
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Summary:	Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease caused by loss of activity of α-l-iduronidase and attendant accumulation of the glycosaminoglycans dermatan sulfate and heparan sulfate. Current treatments are suboptimal and do not address residual disease including corneal clouding, skeletal deformities, valvular heart disease, and cognitive impairment. We treated neonatal dogs with MPS I with intravenous recombinant α-l-iduronidase replacement therapy at the conventional 0.58 mg/kg or a higher 1.57 mg/kg weekly dose for 56 to 81 weeks. In contrast to previous results in animals and patients treated at a later age, the dogs failed to mount an antibody response to enzyme therapy, consistent with the induction of immune tolerance in neonates. The higher dose of enzyme led to complete normalization of lysosomal storage in the liver, spleen, lung, kidney, synovium, and myocardium, as well as in the hard-to-treat mitral valve. Cardiac biochemistry and function were restored, and there were improvements in skeletal disease as shown by clinical and radiographic assessments. Glycosaminoglycan levels in the brain were normalized after intravenous enzyme therapy, in the presence or absence of intrathecal administration of recombinant α-l-iduronidase. Histopathological evidence of glycosaminoglycan storage in the brain was ameliorated with the higher-dose intravenous therapy and was further improved by combining intravenous and intrathecal therapy. These findings argue that neonatal testing and early treatment of patients with MPS I may more effectively treat this disease.
ISSN:	1946-6242
DOI:	10.1126/scitranslmed.3001380