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Abstract：
Gaucher disease (GD), an autosomal recessive lipid storage disorder, arises from mutations in the GBA1 (β-glucocerebrosidase) gene, resulting in glucosylceramide accumulation in tissue macrophages. Lyso-Gb1 (glucosylsphingosine, lyso-GL1), a downstream metabolic product of glucosylceramide, has been identified as a promising biomarker for the diagnosis and monitoring of patients with GD. This retrospective, exploratory analysis of data from phase 3 clinical trials of velaglucerase alfa in patients with type 1 GD evaluated the potential of lyso-Gb1 as a specific and sensitive biomarker for GD. A total of 22 treatment-naïve patients and 21 patients previously treated with imiglucerase (switch patients) were included in the analysis. Overall, demographics between the two groups were similar. Mean lyso-Gb1 concentrations were reduced by 302.2ng/mL from baseline to week 209 in treatment-naïve patients and by 57.3ng/mL from baseline to week 161 in switch patients, corresponding to relative reductions of 82.7% and 52.0%, respectively. In both the treatment-naïve and switch groups, baseline mean lyso-Gb1 was higher for patients with at least one N370S mutation (363.9ng/mL and 90.7ng/mL, respectively) than for patients with non-N370S mutations (184.6ng/mL and 28.3ng/mL, respectively). Moderate correlations between decreasing lyso-Gb1 levels and increasing platelet counts, and with decreasing spleen volumes, were observed at some time points in the treatment-naïve group but not in the switch group. These findings support the utility of lyso-Gb1 as a sensitive and reliable biomarker for GD, and suggest that quantitation of this biomarker could serve as an indicator of disease burden and response to treatment.
摘要：
戈谢病（GD），常染色体隐性脂质贮积症，源于GBA1（β-葡糖脑苷脂酶）基因的突变，导致葡萄糖神经酰胺在组织巨噬细胞中积累。Lyso-Gb1（葡萄糖鞘氨醇，lyso-GL1)，葡萄糖神经酰胺的下游代谢产物，已被确定为诊断和监测GD患者的有希望的生物标志物。这次回顾，对1型GD患者的3期velaglucerasealfa临床试验数据的探索性分析评估了lyso-Gb1作为GD特异性和敏感性生物标志物的潜力。在分析中包括总共22个未治疗的患者和21个先前用亚胺酶治疗的患者(转换患者)。总的来说,两组之间的人口统计学相似。在未接受治疗的患者中，平均lyso-Gb1浓度从基线到第209周降低了302.2ng/mL，在转换患者中，从基线到第161周降低了57.3ng/mL。对应于82.7%和52.0%的相对减少，分别。在幼稚治疗组和转换组中，至少有一个N370S突变的患者的基线平均lyso-Gb1较高(363.9ng/mL和90.7ng/mL,分别）与非N370S突变患者（184.6ng/mL和28.3ng/mL，分别)。降低lyso-Gb1水平和增加血小板计数之间的中等相关性，随着脾脏体积的减少，在未治疗组的某些时间点观察到，但在转换组中没有观察到。这些发现支持lyso-Gb1作为GD的敏感和可靠的生物标志物的实用性，并表明该生物标志物的定量可以作为疾病负担和治疗反应的指标。
