The objective of this ongoing study is to evaluate and delineate the long-term therapeutic effects of enzyme replacement therapy in Gaucher disease in affected children and adults. In addition, efforts are directed to identifying and delineating the causes for and treatment of adverse events related to enzyme therapy, as well as determining the effective dose in individual patients. To date, we have enrolled over forty patients in this protocol from the Cincinnati greater metropolitan area and from around the world. We have established normative data for the expected responses for patients during the first six, twelve and twenty-four months of therapy using either Ceredase (alglucerase for injection from placenta) or Cerezyme (imiglucerase for injection from recombinant sources), and have found that the responses are no different in either treatment group. The same degree of variability, which is very high, is observed with both of the drugs and we have found no specific correlation with age of onset or initiation of therapy, genotype of the individual patients, ethnic extraction, nor initial severity of disease. In general, the hepatic and splenic volumes decrease to about twenty to forty percent of initial volume by two years, the hematologic abnormalities including anemia and thrombocytopenia diminish and become normalized within approximately two to three years, and, in children with growth retardation, normal growth patterns are reestablished within two years. Documentation of improvement in architectural bone disease has been slow and unconvincing. Indeed, based on this result, we have initiated a new protocol that evaluates the effectiveness of alendronate in combination with enzyme therapy on the architectural bone disease in osteopenia of Gaucher disease. Approximately three to five percent of our patients develop minor adverse events, including hives, pruritis, erythema, and headache during or shortly following the infusion. These are managed by decreasing infusion rates and/or pretreatment with antihistamine. We have had no anaphylactic or anaphylactoid reactions. Of the fifteen percent of treated patients that develop antibodies during the course of therapy, two were found to have neutralizing antibodies that altered their responsiveness to enzyme therapy. In both cases, poor to absent response to enzyme infusions was noted and this led to the detection of the neutralizing antibodies. In one patient, a very high dose cytoxin protocol was used to induce tolerance. After two and a half years of high dose therapy, she has tolerized with the absence of both antibodies and neutralizing activity. Ongoing studies are directed to defining the time for tolerization in all patients who develop antibodies; currently this appears to be about twenty-two to twenty-four months. In addition, ongoing studies are directed to defining the parameters that account for the massive variability and response to enzyme therapy in affected patients.
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