Identification Of Clinical Markers

Clinical markers with predictive or prognostic value would be attractive if quantifiable and if assessment is non-tnvasive. It was hoped that the use of animal models would be illustrative of human conditions. In a most recent study of murine MPS I, although it was clearly shown that thickened aortic valves and abnormal cardiac function can be monitored from the preclinical stage, the authors note that "murine MPS I is not identical to human MPS I" - 27] - each has unique clinical features. Nonetheless, a more recent study in murine MPS I employing proteomic analysis of heparin cofactor II-thrombin (HCII-T), which is a serine protease inhibitor, showed highly elevated serum levels in mice and in human patients that were correlated with disease severity and responsive to therapy [28]. HCII-T, therefore, may indeed meet the requirements of a good biomarker for MPS I, especially since it implicates a specific pathophysiology. A second good example in the MPSs is the use of accumulation of a disaccharide (HNS-UA), a marker of heparin sulfate storage in disease - specific sites of MPS IIIA [29] because the rate of accumulation is commensurate with disease severity at these sites and is appropriately reactive to disease - specific therapy.

Along these lines, therefore, it is commendable to find disease- specific parameters that lend themselves to quantification and test correlation with clinical severity and responsiveness to therapy. Biopsies and bone marrow aspirations or repeat radiological workups to stage severity should not be condoned if there is a better option: even, some might say, if that option does not exactly meet our criteria of a "good" biomarker. In Gaucher disease, because of concern about Gaucher-related skeletal involvement as associated with considerable morbidity, one study showed a reduction in osteoblast and osteoclast bone markers [30], but there was no correlation with incidence of bone pathology [31]. Biomarkers in this sense therefore might be misleading. Another example in Fabry disease showed no correlation between plasma concentrations of endothelial markers or homocysteine with response to therapy, although the endothelial and leucocyte activation are good measures of renal and cardiovascular involvement in Fabry disease [32].

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Project Management Made Easy

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