A novel preclinical model of mucopolysaccharidosis type II for developing human hematopoietic stem cell gene therapy
A novel preclinical model of mucopolysaccharidosis type II for developing human hematopoietic stem cell gene therapy
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DOI：
10.1038/s41434-022-00357-y
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发表时间：
2022-07-14
期刊：
影响因子：
5.1
通讯作者：
Kobayashi，Hiroshi
中科院分区：
文献类型：
--
作者：
Shimada，Yohta;Ishii，Natsumi;Kobayashi，Hiroshi
利用慢病毒载体的造血干细胞(HSC)基因治疗(GT)作为治疗神经性溶酶体贮积性疾病的一种有前途的方法已引起人们的兴趣。为了进行HSC-GT的临床开发，体内评价基因转导的人CD34+(hCD34+)细胞的治疗潜力是进行人体试验之前的关键问题之一。在这里，我们建立了一种免疫缺陷的小鼠粘多糖病II型(MPS II)模型，这是一种可移植的人类细胞，并展示了这些小鼠在评估基因修饰的hCD34+细胞治疗效果方面的应用。用CRISPR/Cas9产生的NOG/MPS II小鼠表现出致病酶艾杜酸-2-硫酸酯酶(IDS)活性降低和糖胺多糖在其组织中的积聚。当我们将携带入侵检测基因的慢病毒载体转导的hCD34+细胞移植到NOG/MPS II小鼠体内时，在这些小鼠的内脏和神经组织中观察到了明显的生化病理表型改善。此外，在NOG/MPS II小鼠体内的移植细胞显示了该载体的寡克隆整合模式，但在小鼠体内没有检测到明显的克隆优势。我们的发现表明，NOG/MPS II小鼠在利用人类细胞进行MPS II的HSC-GT的临床前研究中具有良好的应用前景。
A hematopoietic stem cell (HSC) gene therapy (GT) using lentiviral vectors has attracted interest as a promising treatment approach for neuropathic lysosomal storage diseases. To proceed with the clinical development of HSC-GT, evaluation of the therapeutic potential of gene-transduced human CD34+ (hCD34+) cells in vivo is one of the key issues before human trials. Here, we established an immunodeficient murine model of mucopolysaccharidosis type II (MPS II), which are transplantable human cells, and demonstrated the application of those mice in evaluating the therapeutic efficacy of gene-modified hCD34+ cells. NOG/MPS II mice, which were generated using CRISPR/Cas9, exhibited a reduction of disease-causing enzyme iduronate-2-sulfatatase (IDS) activity and the accumulation of glycosaminoglycans in their tissues. When we transplanted hCD34+ cells transduced with a lentiviral vector carrying the IDS gene into NOG/MPS II mice, a significant amelioration of biochemical pathophenotypes was observed in the visceral and neuronal tissues of those mice. In addition, grafted cells in the NOG/MPS II mice showed the oligoclonal integration pattern of the vector, but no obvious clonal dominance was detected in the mice. Our findings indicate the promising application of NOG/MPS II mice to preclinical study of HSC-GT for MPS II using human cells.