Protonged expression of a tysosomat enzyme in mouse tiver after Sleeping Beauty transposon-mediated gene detivery:: imptications for non-virat gene therapy of mucopotysaccharidoses

被引:83
作者
Aronovich, Elena L.
Bell, Jason B.
Belur, Lalitha R.
Gunther, Roland
Koniar, Brenda
Erickson, David C. C.
Schachem, Patricia A.
Matise, Ilze
McIvor, R. Scott
Whitley, Chester B.
Hackett, Perry B.
机构
[1] Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA
[2] Univ Minnesota, Arnold & Mabel Beckman Ctr Transposon Res, Minneapolis, MN 55455 USA
[3] Univ Minnesota, Res Anim Resources, Minneapolis, MN 55455 USA
[4] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA
[5] Univ Minnesota, Dept Otolaryngol, Minneapolis, MN 55455 USA
[6] Univ Minnesota, Ctr Canc, Minneapolis, MN 55455 USA
[7] Univ Minnesota, Inst Human Genet, Minneapolis, MN 55455 USA
关键词
alpha-L-iduronidase; beta-glucuronidase; immune response; inherited disease; animal model;
D O I
10.1002/jgm.1028
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
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.
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收藏
页码:403 / 415
页数:13
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