Discovery of Correction In Vitro Uptake and Treatment of MPS I

In 1969, Frantantoni and Neufeld discovered that secretions of normal cells and normal human urine contained "corrective factors" that, when added to Hurler fibroblasts, could correct the metabolic defect behind the GAG accumulation [3]. Although they did not know initially that this factor was an enzyme, it was clear that it was a diffusible factor and that it was very potent at very low concentrations. By 1971, the identity of the corrective factor for MPS I was determined to be a-L-iduronidase [4], which was modified in some manner that made it distinct on heparin chromatography from noncorrective enzyme [24]. In 1977, Kaplan, et al. [25] determined that the modification that allowed for a-L-iduroni-dase to be corrective was a mannose 6-phosphate moiety on the N-linked high-mannose carbohydrates. Even with both the identity of the enzyme and the reason for its corrective properties known, the ability to test ERT in MPS I was limited by the lack of available sources of appropriately modified enzyme. Enzyme from tissue sources lacked mannose 6-phosphate and was not corrective. In addition, the native enzyme was present in vanish-ingly small quantities in tissues. It took considerable effort and several years to purify 5 |g of native canine iduronidase in order to microsequence and clone the enzyme [26]. The development and study of ERT would have to wait for a recombinant enzyme source.

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