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慢病毒介导的基因疗法治疗小鼠III型黏多糖贮积症A亚型

Lentiviral-mediated gene therapy for murine mucopolysaccharidosis type IIIA.

作者信息

McIntyre Chantelle, Derrick Roberts Ainslie Lauren, Ranieri Enzo, Clements Peter Roy, Byers Sharon, Anson Donald S

机构信息

Department of Genetic Medicine, Women's and Children's Hospital, Children, Youth and Women's Health Service, 72 King William Road, North Adelaide, Adelaide, SA 5006, Australia.

出版信息

Mol Genet Metab. 2008 Apr;93(4):411-8. doi: 10.1016/j.ymgme.2007.11.008. Epub 2008 Jan 8.

Abstract

Mucopolysaccharidosis type IIIA (MPS IIIA) is a heritable glycosaminoglycan (GAG) storage disorder which is characterised by lysosomal accumulation of heparan sulphate, secondary to a deficiency of sulphamidase (heparan-N-sulphatase, N-sulphoglucosamine sulphohydrolase, EC No. 3.10.1.1.). There is currently no treatment for affected individuals who experience progressive CNS deterioration prior to an early death. As a first step towards developing gene therapy as a treatment for MPS IIIA, an MPS IIIA mouse model was used to examine the efficacy of intravenous lentiviral-mediated gene therapy. Five-week-old mice were injected with virus expressing murine sulphamidase and analysed 6 months after treatment. Transduction by the lentiviral vector was highest in the liver and spleen of treated animals, and sulphamidase activity in these tissues averaged 68% and 186% of normal, respectively. Storage was assessed using histochemical, chemical and mass spectrometric analyses. Storage in most somatic tissues was largely normalised, although chondrocytes were an obvious exception. Histologically, improvement of lysosomal storage within the brain was variable. However, beta-hexosaminidase activity, which is abnormally elevated in MPS IIIA, was significantly reduced in every treated tissue, including the brain. Total uronic acid was also significantly reduced in the brains of treated mice. The level of a disaccharide marker (hexosamine-N-sulphate[alpha-1,4]hexuronic acid; HNS-UA) of heparan sulphate storage was also decreased in the brains of treated mice, albeit non-significantly. These results suggest that lentiviral-mediated somatic gene transfer may affect not only the somatic, but possibly also the CNS pathology, found in MPS IIIA.

摘要

ⅢA型黏多糖贮积症(MPS IIIA)是一种遗传性糖胺聚糖(GAG)贮积症,其特征是由于硫酸酰胺酶(乙酰肝素-N-硫酸酯酶、N-硫酸葡糖胺硫酸水解酶,EC编号3.10.1.1)缺乏,导致硫酸乙酰肝素在溶酶体中蓄积。目前,对于在早亡前出现进行性中枢神经系统退化的患者,尚无治疗方法。作为开发基因疗法治疗MPS IIIA的第一步,使用MPS IIIA小鼠模型来检验静脉注射慢病毒介导的基因疗法的疗效。对5周龄小鼠注射表达鼠硫酸酰胺酶的病毒,并在治疗6个月后进行分析。慢病毒载体在治疗动物的肝脏和脾脏中的转导效率最高,这些组织中的硫酸酰胺酶活性分别平均为正常水平的68%和186%。使用组织化学、化学和质谱分析评估蓄积情况。尽管软骨细胞是明显的例外,但大多数体细胞组织中的蓄积情况在很大程度上恢复正常。从组织学上看,脑内溶酶体蓄积的改善情况各不相同。然而,在每个治疗组织(包括脑)中,MPS IIIA中异常升高的β-己糖胺酶活性均显著降低。治疗小鼠脑内的总糖醛酸也显著降低。治疗小鼠脑内硫酸乙酰肝素蓄积的二糖标志物(己糖胺-N-硫酸[α-1,4]己糖醛酸;HNS-UA)水平也有所下降,尽管不显著。这些结果表明,慢病毒介导的体细胞基因转移可能不仅影响MPS IIIA中的体细胞病理,还可能影响中枢神经系统病理。

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