Hematopoietic stem- and progenitor-cell gene therapy

Hematopoietic stem- and progenitor-cell gene therapy for Hurler syndrome

Interim trial results indicate that gene therapy using autologous hematopoietic stem and progenitor cells (HSPCs) is a promising treatment for Hurler syndrome (mucopolysaccharidosis type I, Hurler variant [MPSIH]). The ongoing study includes eight pediatric patients with no viable donors for allogeneic hematopoietic stem-cell transplantation, the current standard of care. All eight received HSPCs transduced ex vivo with an alpha-L-iduronidase (IDUA)-encoding lentiviral vector, which triggered significant metabolic repair in peripheral tissues and in central nervous system. Prompt and sustained engraftment of gene-corrected cells was observed participants, all of whom also achieved supraphysiologic blood IDUA activity within 1 month and successfully maintained it. Previously undetectable levels of IDUA activity in the cerebrospinal fluid became detectable following gene therapy. The higher levels correlated to local clearance of urinary gloycosaminoglycan excretion, which fell to normal volumes in four of the five patients who could be evaluated at 12 months. Meanwhile, cognitive function remained stable in the children, none of whom presented with moderate or severe cognitive impairment at baseline. Just over 2 years into their planned 5-year study, researchers report that the safety profile of HSPC therapy closely mimics that of allo-HSCT, which is only partially effective in this setting and is associated with complications. 

Hurler 综合征的造血干细胞和祖细胞基因治疗
中期试验结果表明，使用自体造血干细胞和祖细胞 (HSPC) 的基因疗法是治疗 Hurler 综合征（I 型粘多糖贮积症，Hurler 变异 [MPSIH]）的有希望的治疗方法。正在进行的研究包括八名没有可行供体的儿科患者进行同种异体造血干细胞移植，这是目前的护理标准。所有八人都接受了用α-L-艾杜糖苷酸酶（IDUA）编码慢病毒载体离体转导的HSPC，这在外周组织和中枢神经系统中引发了显着的代谢修复。观察到参与者迅速且持续地植入基因校正细胞，所有这些参与者也在 1 个月内实现了超生理血液 IDUA 活性并成功维持了它。基因治疗后，脑脊液中以前无法检测到的 IDUA 活性水平变得可检测到。较高的水平与尿糖胺聚糖排泄物的局部清除相关，在 12 个月时可评估的五名患者中有四名患者的尿糖胺聚糖排泄物降至正常量。同时，儿童的认知功能保持稳定，在基线时没有人出现中度或重度认知障碍。在他们计划的 5 年研究刚刚过去 2 年多的时间里，研究人员报告说，HSPC 治疗的安全性与 allo-HSCT 非常相似，后者在这种情况下仅部分有效并且与并发症相关。