Iduronidase

Aldurazyme (tradename, also known as laronidase) is a recombinant version of one polymorphic variant of the human enzyme a-L-iduronidase. It was approved for general medical use in the USA in 2003 and is indicated for the treatment of patients with certain forms of the rare inherited disease MPS I. MPS I is caused by a deficiency of a lysosomal a-L-iduronidase, which normally catalyses the hydrolysis of terminal a-L-iduronic acid residues from the glycosaminoglycans dermatan sulfate and heparin sulfate. The deficiency results in accumulation of the glycosaminoglycans throughout the body, causing widespread cell and tissue dysfunction. 

I Hurler Autosomal recessive Ol-L-iduronidase Dermatan sulfate... 

Hurler syndrome (MPS type I) is caused by deficiency of a-iduronidase, a lysosomal enzyme involved In degradation of dermatan sulfate and heparan sulfate, which accumulate in the cells of all tissues and spill over into the urine. 

Laronidase (Aldurazyme) is recombinant-L-idu-ronidase. In mucopolysaccharidosis I (Hurler syndrome) there is a deficiency of the lysosomal enzyme a -L-iduronidase. Laronidase is employed for the non-neurological manifestations of Hurler syndrome. After intravenous infusion laronidase is eliminated with a half-life of 1.5-3.6 hours. Infusion related side effects are seen frequently. Hypersensitivity reactions may occur. 

See section 4.1.3.4, subheading Calculation. As iduronidase activity is rather low in leukocytes, results should be expressed as nmol/h-mg protein. 

Iduronidase solution lyophilized lysosomal enzymes purified from bovine testis (Moscerdam Substrates) are reconstituted in 2.2 ml demineralized water and aliquots are stored at -80°C. 

For the measurement of a-iduronidase activity, a novel substrate was developed that was detected by mass spectrometry. It was possible to combine this method with similar assays for Niemann-Pick type A/ , Krabbe, Gaucher, Pompe, and Fabry disease. However, separate incubation is necessary, and some additional work-up procedures are usually required to purify the sample before mass spectrophotomet-ric analysis [68]. 

Chamoles NA, Blanco M, Gaggioli D (2001) Diagnosis of a-L-iduronidase deficiency in dried blood spots on filter paper the possibility of newborn diagnosis. Clin Chem 47 780-781... 

Stirling JL, Robinson D, Fensom AH, Benson PF, Baker JE, Button LR (1979) Prenatal diagnosis of two Hurler fetuses using an improved assay for methylumbelliferyl-a-L-iduronidase. Lancet 2 37... 

This "Hurler corrective factor" was identified as an a-L-iduronidase. In the Hunter syndrome (MPS II) dermatan sulfate and heparan sulfate accumulate. 

MPS I (Hurler) a-l-Iduronidase Dermatan sulfate, heparan sulfate Skeletal, organomegaly, cardiovascular, neurological, ocular Cat, dog, mouse Retrovirus Ex-vivo (Zheng et al., 2004) in utero (Meertens et al., 2002) Plasmid IM (Lutzko et al., 1999) AAV Intracranial (Desmaris et al., 2004) IV (Hartung et al., 2004)... 

Hartung, S. D., Frandsen, J. L., Pan, D., Koniar, B. L., Graupman, P., Gunther, R., Low, W. C., Whitley, C. B. and Mclvor, R. S. (2004). Correction of metabolic, craniofacial, and neurologic abnormalities in MPS I mice treated at birth with adeno-associated virus vector transducing the human alpha-L-iduronidase gene. Mol. Ther. 9, 866-875. 

Genetically corrected autologous stem cells engraft, but host immune responses limit their utility in canine alpha-L-iduronidase deficiency. Blood 93, 1895-1905. 

Meertens, L., Zhao, Y., Rosic-Kablar, S., Li, L., Chan, K., Dobson, H., Gartley, C., Lutzko, C., Hopwood, J., Kohn, D., Kruth, S., Hough, M. R. and Dube, I. D. (2002). In utero injection of alpha-L-iduronidase-carrying retrovirus in canine mucopolysaccharidosis type I Infection of multiple tissues and neonatal gene expression. Hum. Gene Ther. 13, 1809-1820. 

Wraith, J. E., Clarke, L. A., Beck, M., Kolodny, E. H., Pastores, G. M., Muenzer, J., Rapoport, D. M., Berger, K. I., Swiedler, S. J., Kakkis, E. D., Braakman, T., Chadbourne, E., Walton-Bowen, K. and Cox, G. F. (2004). Enzyme replacement therapy for mucopolysaccharidosis I A randomized, double-blinded, placebo-controlled, multinational study of recombinant human alpha-L-iduronidase (laronidase). J. Pediatr. 144, 581-588. 

Aldurazyme polymorphic variation of human a-L-iduronidase lysosomal hydrolase hydrolysis of terminal a-L-iduronic acid residues of dermatan sulfate and heparin sulfate No genotoxicity studies clinical trials Studies to assess mutagenic and carcinogenic potential have not been conducted No warnings or precautions regarding carcinogenic risk... 

Canine MPS I was discovered in a Plott hound that presented with corneal clouding [10]. Studies by Shull and Neufeld showed that the dogs were deficient in a-l-iduronidase [11], Being null, MPS I dogs are genetically similar to the most severe form of MPS I in humans, but clinically they more closely resemble moderately affected patients. These animals provide a valuable bio-chemical/clinical model for MPS I disease. Since they have no confounding residual enzyme activity, they accumulate GAGs in relevant tissues, and their clinical phenotype closely resembles the human disease. 

MPS I dogs were used to evaluate the biodistribution of rh-iduronidase, pharmacodynamic reduction of tissue GAGs and in vivo efficacy. Pharmacokinetics and the effects of various doses and regimens of rh-iduronidase were also evaluated in this model. Heterozygote dogs from the MPS I colony, referred to as normal carriers, were used to derive normal tissue levels of a-l-iduronidase activity and GAG storage. 

Shull RM, Munger RJ, Spellacy E, Hall CW, Constantopoulos G, Neufeld EF. Canine alpha-L-iduronidase deficiency. A model of mucopolysaccharidosis I. Am J Pathol 1982 109(2) 244-8. 

Spellacy E, Shull RM, Constantopoulos G, Neufeld EF. A canine model of human alpha-l-iduronidase deficiency. Proc Natl Acad Sci USA 1983 80(19) 6091-5. 

Golgi a-l)-mannosidase II lysosomal mannosidase glycoprotein A-linked oligosaccharide processing [toxic, neurotoxic effects mimic hereditary lysosomal storage disease mannosidosis] (3-D-Glucuronidase cx-1-iduronidase Glucosidase... 

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