Chandra Sundeep, Cristofori Patrizia, Fonck Carlos, O'Neill Charles A
1 BioMarin Pharmaceutical Inc., San Rafael, California, USA.
2 GlaxoSmithKline, Hertfordshire, United Kingdom.
Toxicol Pathol. 2019 Jul;47(5):656-660. doi: 10.1177/0192623319844484. Epub 2019 May 7.
A therapeutic option for monogenic disorders is gene therapy with -transduced autologous hematopoietic stem cells (HSCs). Safety or efficacy studies of -modified HSCs are conducted in humanized mouse models after ablation of the murine bone marrow and transfer of human CD34 HSCs. Engrafted human CD34 cells migrate to bone marrow and differentiate into various human hematopoietic lineages. A 12-week study was conducted in NSG™ mice to evaluate engraftment, differentiation, and safety of human CD34 cells that were transduced () with a proprietary lentiviral vector encoding a human gene (BMRN-1) or a mock (green fluorescent protein) vector. Several mice intravenously injected with naive CD34 cells or transduced CD34 cells had variable lymphohistiocytic inflammatory cell infiltrates and microgranulomas in the liver and lungs consistent with graft-versus-host disease (GVHD). Spleen, bone marrow, stomach, reproductive tract, but not the skin had similar inflammatory changes. viral transduction of CD34 cells did not impact engraftment or predispose to xenogeneic GVHD.
单基因疾病的一种治疗选择是用转导的自体造血干细胞（HSCs）进行基因治疗。对经修饰的HSCs进行安全性或有效性研究是在清除小鼠骨髓并移植人CD34+HSCs后，在人源化小鼠模型中进行的。植入的人CD34+细胞迁移到骨髓并分化为各种人类造血谱系。在NSG™小鼠中进行了一项为期12周的研究，以评估用编码人类基因（BMRN-1）的专有慢病毒载体或空载体（绿色荧光蛋白）转导的人CD34+细胞的植入、分化和安全性。几只静脉注射未处理的CD34+细胞或转导的CD34+细胞的小鼠在肝脏和肺中出现了可变的淋巴细胞组织细胞性炎性细胞浸润和微肉芽肿，与移植物抗宿主病（GVHD）一致。脾脏、骨髓、胃、生殖道，但皮肤没有类似的炎症变化。CD34+细胞的病毒转导不影响植入或引发异种GVHD。
