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首页> 外文期刊>The journal of gene medicine >Protonged expression of a tysosomat enzyme in mouse tiver after Sleeping Beauty transposon-mediated gene detivery: imptications for non-virat gene therapy of mucopotysaccharidoses
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Protonged expression of a tysosomat enzyme in mouse tiver after Sleeping Beauty transposon-mediated gene detivery: imptications for non-virat gene therapy of mucopotysaccharidoses

机译：睡美人转座子介导的基因诱变后，小鼠细颈动物中tysosomat酶的增强表达：粘多糖的非病毒基因治疗的意义

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Background The Sleeping Beauty (SB) transposon system is a non-viral vector system that can integrate precise sequences into chromosomes. We evaluated the SB transposon system as a tool for gene therapy of mucopolysaccharidosis (MPS) types I and VII. Methods We constructed SB transposon plasmids for high-level expression of human beta-glucuronidase (hGUSB) or alpha-L-iduronidase (hIDUA). Plasmids were delivered with and without SB transposase to mouse liver by rapid, high-volume tail-vein injection. We studied the duration of expressed therapeutic enzyme activity, transgene presence by PCR, lysosomal pathology by toluidine blue staining and cell-mediated immune response histologically and by immunohistochemical staining. Results Transgene frequency, distribution of transgene and enzyme expression in liver and the level of transgenic enzyme required for amelioration of lysosomal pathology were estimated in NIPS I and VII mice. Without immunomodulation, initial GUSB and IDUA activities in plasma reached >100-fold of wild-type (WT) levels but fell to background within 4 weeks post-injection. In immunomodulated transposon-treated MPS I mice plasma IDUA persisted for over 3 months at up to 100-fold WT activity in one-third of MPS I mice, which was sufficient to reverse lysosomal pathology in the liver and, partially, in distant organs. Histological and immunohistochemical examination of liver sections in IDUA transposon-treated WT mice revealed inflammation 10 days post-injection consisting predominantly of mononuclear cells some of which were CD4- or CD8- positive. Conclusions Our results demonstrate the feasibility of achieving prolonged expression of lysosomal enzymes in the liver and reversing MPS disease in adult mice with a single dose of therapeutic SB transposons. Copyright (C) 2007 John Wiley & Sons, Ltd.
机译：背景睡美人（SB）转座子系统是一种非病毒载体系统，可以将精确的序列整合到染色体中。我们评估了SB转座子系统作为I型和VII型粘多糖贮积病（MPS）基因治疗的工具。方法我们构建了SB转座子质粒，用于高水平表达人β-葡糖醛酸糖苷酶（hGUSB）或α-L-艾杜糖醛酸酶（hIDUA）。通过快速，大量尾静脉注射，将带有或不带有SB转座酶的质粒递送至小鼠肝脏。我们研究了表达的治疗性酶活性的持续时间，通过PCR的转基因存在，通过甲苯胺蓝染色的溶酶体病理学以及组织学和免疫组织化学染色的细胞介导的免疫应答。结果在NIPS I和VII小鼠中估计了肝中的转基因频率，转基因的分布和酶表达以及改善溶酶体病理学所需的转基因酶水平。如果不进行免疫调节，血浆中的初始GUSB和IDUA活性达到野生型（WT）水平的> 100倍，但在注射后4周内降至本底。在经免疫调节的转座子处理的MPS I小鼠中，血浆IDUA在三分之一的MPS I小鼠中以高达100倍的WT活性持续3个月以上，足以逆转肝脏以及部分器官的溶酶体病理。在IDUA转座子治疗的WT小鼠中，肝脏切片的组织学和免疫组化检查显示，注射后10天出现炎症，主要由单核细胞组成，其中一些是CD4或CD8阳性。结论我们的结果证明了用单剂量的SB转座子治疗成年小鼠肝中溶酶体酶的延长表达和逆转MPS疾病的可行性。版权所有（C）2007 John Wiley＆Sons，Ltd.

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