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首页> 美国卫生研究院文献>Molecular Therapy >Efficacy of a Combined Intracerebral and Systemic Gene Delivery Approach for the Treatment of a Severe Lysosomal Storage Disorder
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Efficacy of a Combined Intracerebral and Systemic Gene Delivery Approach for the Treatment of a Severe Lysosomal Storage Disorder

机译：结合脑和全身基因传递方法治疗严重的溶酶体贮积症的功效

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Multiple sulfatase deficiency (MSD), a severe autosomal recessive disease is caused by mutations in the sulfatase modifying factor 1 gene (Sumf1). We have previously shown that in the Sumf1 knockout mouse model (Sumf1−/−) sulfatase activities are completely absent and, similarly to MSD patients, this mouse model displays growth retardation and early mortality. The severity of the phenotype makes MSD unsuitable to be treated by enzyme replacement or bone marrow transplantation, hence the importance of testing the efficacy of novel treatment strategies. Here we show that recombinant adeno-associated virus serotype 9 (rAAV9) vector injected into the cerebral ventricles of neonatal mice resulted in efficient and widespread transduction of the brain parenchyma. In addition, we compared a combined, intracerebral ventricles and systemic, administration of an rAAV9 vector encoding SUMF1 gene to the single administrations—either directly in brain, or systemic alone —in MSD mice. The combined treatment resulted in the global activation of sulfatases, near-complete clearance of glycosaminoglycans (GAGs) and decrease of inflammation in both the central nervous system (CNS) and visceral organs. Furthermore, behavioral abilities were improved by the combined treatment. These results underscore that the “combined” mode of rAAV9 vector administration is an efficient option for the treatment of severe whole-body disorders.
机译：多种硫酸酯酶缺乏症（MSD）是一种严重的常染色体隐性遗传疾病，是由硫酸酯酶修饰因子1基因（Sumf1）的突变引起的。先前我们已经证明，在Sumf1基因敲除小鼠模型（Sumf1 -/-）中，硫酸酯酶活性完全不存在，并且与MSD患者相似，该小鼠模型显示出生长迟缓和早期死亡。该表型的严重性使得MSD不适合通过酶替代或骨髓移植进行治疗，因此测试新型治疗策略疗效的重要性。在这里，我们显示了重组腺相关病毒血清型9（rAAV9）载体注入新生小鼠的脑室导致了脑实质的有效和广泛的转导。此外，我们将合并SUM1基因的rAAV9载体的脑室内和全身给药与MSD小鼠的单次给药（直接在大脑中或单独全身给药）进行了比较。联合治疗导致了硫酸酯酶的全面活化，糖胺聚糖（GAG）的接近完全清除以及中枢神经系统（CNS）和内脏器官炎症的减轻。此外，通过联合治疗可以改善行为能力。这些结果表明，rAAV9载体给药的“联合”模式是治疗严重全身疾病的有效选择。

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