Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-5810, Japan.
Blood. 2013 Apr 18;121(16):3267-73. doi: 10.1182/blood-2012-07-443713. Epub 2013 Feb 14.
Hematopoietic stem cell (HSC) gene therapy is a potentially curative treatment modality for monogenic hematological diseases and storage disorders. It is necessary, however, to establish pre-bone marrow (BM) transplant conditioning regimens that minimize DNA damage and toxicity. Type I interferon (IFN) signaling activates quiescent HSCs and enables them to be sensitive to 5-fluorouracil (FU)-mediated cytotoxicity, thus implying a molecular basis for improving HSC transplant outcomes. Here we show that type I IFN preconditioning, without irradiation or DNA alkylating agents, significantly enhanced the HSC engraftment efficiency in wild-type (WT) recipient mice. The importance of active type I IFN signaling in HSC recipients was further demonstrated using mice lacking IFN regulatory factor 2 (IRF2), a transcriptional suppressor of type I IFN signaling. In both WT and Irf2(-/-) recipients, active type I IFN signaling greatly enhanced the sensitivity to 5-FU or low-dose irradiation of HSCs. Importantly, IFN-based pre-BM transplant conditioning was also applicable to the treatment of Sly syndrome, a congenital storage disorder with β-glucuronidase deficiency, in which it restored enzyme expression at the HSC level and reciprocally reduced pathological glycosaminoglycan storage. Our findings suggest type I IFN-based preconditioning, combined with HSC transplantation, as a novel nongenotoxic treatment of some congenital diseases.
造血干细胞（HSC）基因治疗是一种治疗单基因血液疾病和储存障碍的潜在治愈方法。然而，有必要建立预先骨髓（BM）移植的预处理方案，以最大限度地减少 DNA 损伤和毒性。I 型干扰素（IFN）信号激活静止的 HSC，并使它们对 5-氟尿嘧啶（FU）介导的细胞毒性敏感，这意味着改善 HSC 移植结果的分子基础。在这里，我们表明 I 型 IFN 预处理，不进行辐射或 DNA 烷化剂，可显著提高野生型（WT）受体小鼠中的 HSC 植入效率。使用缺乏 IFN 调节因子 2（IRF2）的小鼠进一步证明了活跃的 I 型 IFN 信号在 HSC 受体中的重要性，IRF2 是 I 型 IFN 信号的转录抑制剂。在 WT 和 Irf2（-/-）受体中，活跃的 I 型 IFN 信号大大增强了 HSC 对 5-FU 或低剂量辐射的敏感性。重要的是，基于 IFN 的预处理方案也适用于 Sly 综合征的治疗，Sly 综合征是一种先天性储存障碍，缺乏β-葡萄糖醛酸酶，它在 HSC 水平上恢复了酶的表达，并反过来减少了病理性糖胺聚糖的储存。我们的发现表明，I 型 IFN 预处理联合 HSC 移植，作为某些先天性疾病的新型非基因毒性治疗方法。
