Differential Molecular Effects of Imiglucerase and Velaglucerase Alfa in Gaucher Disease Mice [RNA-Seq]

Gaucher disease type 1 is an inborn error of metabolic disease with the defective activity of the lysosomal enzyme acid b-glucosidase (GCase). Enzyme replacement/reconstitution therapy (ERT), infusions with purified recombinant GCases, is efficacious in reversing hematologic, hepatic, splenic, and bony disease manifestations in Gaucher type 1 patients. However, the tissue specific molecular events in Gaucher disease and their response to therapy are not known yet. To explore the molecular events underlying GCase treatment, we evaluated the tissue-specific gene expression profiles and molecular responses in our Gaucher disease mouse model, which were treated with two FDA approved commercially available GCases, imiglucerase (imig) and velaglucerase alfa (vela). Using microarray and mRNA-Seq techniques, differentially expressed genes (DEGs) were identified in the spleen and liver by the direct comparison of imig- vs. vela- treated mice. Among them three gene expression networks were derived from these spleens: 1) cell division/proliferation, 2) hematopoietic system and 3) inflammatory/macrophage response. Our study showed the occurrence of differential molecular pathophysiologic processes in the mice treated with imig compared with vela even though these two biosimilars had the same histological and biochemical efficacy Overall design: 9V/null mice (Gaucher mouse model) were injected weekly via tail vein with 60U/kg/wk of imig or vela for 8 wks. To understand the molecular events underlying GCase treatment, we evaluated the tissue-specific gene expression profiles and molecular responses in our Gaucher disease mouse model, which were treated with two FDA approved commercially available GCases, imiglucerase (imig) and velaglucerase alfa (vela).

戈谢病1型是一类先天性代谢异常疾病，其病因在于溶酶体酸性β-葡萄糖苷酶（acid b-glucosidase, GCase）活性缺陷。酶替代/重构疗法（Enzyme replacement/reconstitution therapy, ERT）通过静脉输注纯化重组GCase制剂，可有效逆转戈谢病1型患者的血液学、肝脏、脾脏及骨骼病变表现。然而，戈谢病中组织特异性分子事件及其对治疗的应答机制目前仍未明确。
为探究GCase治疗背后的分子事件，我们在经两种FDA获批的商用GCase制剂——伊米苷酶（imiglucerase, imig）与维拉苷酶α（velaglucerase alfa, vela）——治疗的戈谢病小鼠模型中，评估了组织特异性基因表达谱与分子应答。本研究采用微阵列（microarray）与mRNA测序（mRNA-Seq）技术，通过直接比较伊米苷酶治疗组与维拉苷酶α治疗组小鼠的脾脏与肝脏组织，筛选得到差异表达基因（differentially expressed genes, DEGs）。其中从脾脏样本中衍生出3个基因表达调控网络：1）细胞分裂/增殖；2）造血系统；3）炎症/巨噬细胞应答。本研究发现，尽管这两种生物类似药具有相同的组织学与生化疗效，但伊米苷酶治疗组小鼠与维拉苷酶α治疗组小鼠间存在差异化的分子病理生理过程。
实验设计：将9V/null小鼠（戈谢病小鼠模型）经尾静脉每周注射60U/kg/周的伊米苷酶或维拉苷酶α，持续8周。为明确GCase治疗背后的分子事件，我们在经两种FDA获批商用GCase制剂——伊米苷酶与维拉苷酶α——治疗的戈谢病小鼠模型中，评估了组织特异性基因表达谱与分子应答。