Neonatal gene transfer leads to widespread correction of pathology in a murine model of lysosomal storage disease
Neonatal gene transfer leads to widespread correction of pathology in a murine model of lysosomal storage disease
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DOI：
10.1073/pnas.96.5.2296
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发表时间：
1999-03-02
影响因子：
11.1
通讯作者：
Sands, MS
中科院分区：
文献类型：
--
作者：
Daly, TM;Vogler, C;Sands, MS
对于许多先天性代谢缺陷，早期治疗对于预防长期发育后遗症至关重要，Ne已经使用基因治疗方法在粘多糖沉积症VII型（MPS VII）的小鼠模型中证明了这一概念。新生MPS VII小鼠单次静脉注射5.4 × 10（6）感染单位的编码人β-葡萄糖醛酸苷酶（GUSB）cDNA的重组腺相关病毒。到1周龄时，肝脏、心脏、肺、脾脏、肾脏、大脑和视网膜中的GUSB表达达到了治疗水平，在16周的研究持续时间内，GUSB表达在大多数器官中持续存在，其水平足以减少或完全防止溶酶体储存。特别重要的是，中枢神经系统的神经元、小胶质细胞和脑膜几乎没有疾病。此外，MPS VII小鼠的新生儿治疗提供了通过静脉途径进入中枢神经系统的途径，避免了生命后期更具侵入性的手术。这些数据表明，腺相关病毒介导的基因转移可以在生命早期达到治疗相关的酶水平，组织的快速生长和分化不会限制长期表达。
For many inborn errors of metabolism, early treatment is critical to prevent long-term developmental sequelae, Ne have used a gene-therapy approach to demonstrate this concept in a murine model of mucopolysaccharidosis type VII (MPS VII). Newborn MPS VII mice received a single intravenous injection with 5.4 x 10(6) infectious units of recombinant adeno-associated virus encoding the human P-glucuronidase (GUSB) cDNA. Therapeutic levels of GUSB expression were achieved by 1 week of age in liver, heart, lung, spleen, kidney, brain, and retina, GUSB expression persisted in most organs for the 16-week duration of the study at levels sufficient to either reduce or prevent completely lysosomal storage. Of particular significance, neurons, microglia, and meninges of the central nervous system were virtually cleared of disease. In addition, neonatal treatment of MPS VII mice provided access to the central nervous system via an intravenous route, avoiding a more invasive procedure later in life. These data suggest that gene transfer mediated by adenoassociated virus can achieve therapeutically relevant levels of enzyme very early in life and that the rapid growth and differentiation of tissues does not limit long-term expression.