ENZYME AUGMENTATION THERAPY OF GAUCHER DISEASE

这项正在进行的研究的目的是评估和描述酶替代疗法对儿童和成人戈谢病的长期治疗效果。此外，还致力于确定和描述与酶治疗相关的不良事件的原因和治疗，以及确定个体患者的有效剂量。到目前为止，我们已经从辛辛那提大都市区和世界各地招募了40多名患者。我们已经建立了患者在使用Ceredase（来自胎盘的注射用alglucerase）或Cerezyme（来自重组来源的注射用imiglucerase）治疗的前6个月、12个月和24个月预期反应的规范数据，并发现两组患者的反应没有差异。在两种药物中观察到相同程度的变异性，这是非常高的，我们没有发现与发病年龄或开始治疗，个体患者的基因型，种族提取，也没有疾病的初始严重程度的具体相关性。一般来说，肝脏和脾脏的体积在两年内减少到初始体积的20%到40%，血液异常包括贫血和血小板减少症在大约两到三年内减少并恢复正常，而在生长迟缓的儿童中，正常的生长模式在两年内恢复。关于建筑骨病改善的文献记录缓慢且缺乏说服力。事实上，基于这一结果，我们已经启动了一项新的方案，评估阿仑膦酸钠联合酶治疗戈谢病骨质减少的建筑性骨病的有效性。大约3%至5%的患者在输液期间或输液后不久出现轻微不良事件，包括荨麻疹、瘙痒、红斑和头痛。这些可以通过降低输注速率和/或抗组胺预处理来控制。我们没有过敏或类过敏反应。在治疗过程中产生抗体的15%的患者中，有两名患者被发现具有中和抗体，这改变了他们对酶治疗的反应。在这两种情况下，对酶输注的不良反应被注意到，这导致了中和抗体的检测。在一名患者中，使用了非常高剂量的细胞毒素方案来诱导耐受性。经过两年半的高剂量治疗，她已经耐受了抗体和中和活性的缺失。正在进行的研究旨在确定所有产生抗体的患者的耐受时间；目前看来，这大约是22到24个月。此外，正在进行的研究旨在确定影响患者对酶治疗的巨大变异性和反应的参数。

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.