Department of Medicine, Washington University School of Medicine, St Louis, Missouri, USA.
Mol Ther. 2010 Feb;18(2):334-42. doi: 10.1038/mt.2009.236. Epub 2009 Oct 20.
Mucopolysaccharidosis I (MPS I) is a lysosomal storage disease due to deficiency in alpha-L-iduronidase (IDUA) that results in accumulation of glycosaminoglycans (GAGs) throughout the body, causing numerous clinical defects. Intravenous administration of a gamma-retroviral vector (gamma-RV) with an intact long terminal repeat (LTR) reduced the clinical manifestations of MPS I, but could cause insertional mutagenesis. Although self-inactivating (SIN) gamma-RVs in which the enhancer and promoter elements in the viral LTR are absent after transduction reduces this risk, such vectors could be less effective. This report demonstrates that intravenous (i.v.) injection of a SIN gamma-RV expressing canine IDUA from the liver-specific human alpha(1)-antitrypsin promoter into adult or newborn MPS I mice completely prevents biochemical abnormalities in several organs, and improved bone disease, vision, hearing, and aorta to a similar extent as was seen with administration of the LTR-intact vector to adults. Improvements were less profound than when using an LTR-intact gamma-RV in newborns, which likely reflects a lower level of transduction and expression for the SIN vector-transduced mice, and might be overcome by using a higher dose of SIN vector. A SIN gamma-RV vector ameliorates clinical manifestations of MPS I in mice and should be safer than an LTR-intact gamma-RV.
黏多糖贮积症 I（MPS I）是一种溶酶体贮积病，由于α-L-艾杜糖苷酸酶（IDUA）缺乏，导致糖胺聚糖（GAGs）在全身积累，引起多种临床缺陷。静脉内给予带有完整长末端重复序列（LTR）的γ-逆转录病毒载体（γ-RV）可减轻 MPS I 的临床表现，但可能导致插入突变。尽管缺失了病毒 LTR 中的增强子和启动子元件的自我失活（SIN）γ-RV 降低了这种风险，但这种载体的效果可能较差。本报告表明，从肝脏特异性人α1-抗胰蛋白酶启动子表达犬 IDUA 的 SIN γ-RV 通过静脉内（i.v.）注射到成年或新生 MPS I 小鼠体内，可完全防止几种器官的生化异常，并改善骨骼疾病、视力、听力和主动脉，其效果与向成年小鼠给予 LTR 完整载体相似。改善程度不如在新生小鼠中使用 LTR 完整γ-RV 时明显，这可能反映出 SIN 载体转导小鼠的转导和表达水平较低，通过使用更高剂量的 SIN 载体可能会克服这一问题。SIN γ-RV 载体可改善 MPS I 小鼠的临床表现，且应比 LTR 完整γ-RV 更安全。
