Mucopolysaccharidosis I (MPS I) is a lysosomal storage disorder caused by a deficiency of a-L-iduronidase. The deficiency of a-L-iduronidase leads to the accumulation of the glycosaminoglycans (GAGs) heparan sulfate and dermatan sulfate in a wide variety of tissues. Currently, the only treatment available to MPS I patients is bone marrow transplantation (BMT). BMT has demonstrated efficacy in decreasing GAG storage and improving clinical outcome but restricted availability of matched donors, high cost and high morbidity and mortality limits this procedure to only a very few patients. In those BMT patients with adequate engraftment, improvements in liver and spleen storage and urinary GAG excretion over the first few months has been shown to be associated with an improved clinical outcome including less joint stiffness, decreased airway obstruction and less cardiac disease. An adequate dose of enzyme should result in enzyme activity in tissues and reduction in the level of storage product. Based on the kinetics of mannose 6-phosphate dependent uptake in cultured fibroblasts, an enzyme dose of 25,000 units/kg (~0.l mg/kg), is sufficient to raise the extracellular compartment to a concentration exceeding the Kuptake was used in the first preclinical studies. These in vivo studies demonstrated that this dose allowed a time-averaged exposure to the enzyme at concentrations equal to the Kuptake (0.7-l.0nM) for about 1 hour. The slow infusion method used for enzyme administration and the use of albumin as carrier protein were developed during the dog studies. Once antibodies against the human a-L-iduronidase have developed, the dogs are susceptible to a complement-mediated anaphylactoid reaction. By administering a low dose of 3,000 units per kg during the first hour the dogs are protected from the reaction during the second hour when the rest of the enzyme is administered. Failure to include albumin can cause a reaction, which can be prevented in subsequent infusions by its addition at 1 mg/mL. These two modifications have prevented any serious reactions in dogs.
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