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受影响的儿童和成人的高谢病的长期疗效。此外，还致力于确定和描述与酶疗法有关的不良事件的原因和治疗，以及确定个别患者的有效剂量。到目前为止，我们已经从辛辛那提大城市地区和世界各地招募了40多名患者参加该方案。我们已经建立了使用Ceredase(从胎盘注射的ALGERASE)或Cerezyme(来自重组来源的注射用亚糖酶)的患者在治疗的前6个月、12个月和24个月的预期反应的标准数据，并发现这两个治疗组的反应没有区别。在两种药物中都观察到了相同程度的变异性，这是非常高的，我们没有发现与发病年龄或开始治疗、个别患者的基因、种族血统或最初的疾病严重程度没有特定的相关性。一般来说，肝和脾的体积在两年内减少到初始体积的20%到40%，包括贫血和血小板减少在内的血液异常在大约两到三年内减少并恢复正常，对于生长迟缓的儿童，正常的生长模式在两年内恢复。有关建筑性骨病改善的文献进展缓慢，难以令人信服。事实上，基于这一结果，我们已经启动了一项新的方案，评估阿伦磷酸钠与酶疗法联合治疗高谢病骨量减少症的建筑性骨病的有效性。大约3%到5%的患者在输液期间或之后不久会出现轻微的不良反应，包括麻疹、瘙痒、红斑和头痛。这些可以通过降低输液速度和/或抗组胺药物的预处理来处理。我们没有过敏性或类过敏性反应。在治疗过程中产生抗体的15%的接受治疗的患者中，有两人被发现有中和抗体，这改变了他们对酶疗法的反应性。在这两种情况下，注意到对酶注射的反应很差或没有反应，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环磷酰胺方案来诱导耐受。经过两年半的大剂量治疗，她已经耐受了，既没有抗体也没有中和活性。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，这似乎是大约22到24个月。此外，正在进行的研究旨在确定解释受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.