Mucopolysaccharidosis type IIIA (MPS-IIIA) is a lysosomal storage disorder (LSD) caused by inherited defect of sulfamidase, a lysosomal sulfatase. MPS-IIIA is one of the most common and severe forms of LSDs with CNS involvement. Presently there is no cure. Here we have developed a new gene delivery approach for the treatment of MPS-IIIA based on the use of a modified version of sulfamidase expression cassette. This cassette encodes both a chimeric sulfamidase containing an alternative signal peptide (sp) to improve enzyme secretion and sulfatase-modifying factor 1 (SUMF1) to increase sulfamidase post-translational activation rate. We demonstrate that improved secretion and increased activation of sulfamidase act synergistically to enhance enzyme biodistribution in wild-type (WT) pigs upon intrathecal adeno-associated virus serotype 9 (AAV9)-mediated gene delivery. Translating such gene delivery strategy to a mouse model of MPS-IIIA results in a rescue of brain pathology, including memory deficit, as well as improvement in somatic tissues. These data may pave the way for developing effective gene delivery replacement protocols for the treatment of MPS-IIIA patients.

中文翻译：

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增强磺酰胺酶治疗粘多糖贮积症IIIA的治疗潜力。

IIIA型粘多糖贮积病（MPS-IIIA）是由溶酶体硫酸酯酶的磺酰胺酶的遗传缺陷引起的溶酶体贮积病（LSD）。MPS-IIIA是参与CNS的LSD的最常见和最严重的形式之一。目前尚无治愈方法。在这里，我们基于磺酰胺酶表达盒的改良版，开发了一种新的基因递送方法，用于治疗MPS-IIIA。该盒既编码包含替代信号肽（sp）的嵌合磺酰胺酶，以改善酶的分泌，又编码硫酸酯酶修饰因子1（SUMF1），以提高磺酰胺酶的翻译后激活率。我们证明，鞘内腺相关病毒血清型9（AAV9）介导的基因传递在野生型（WT）猪中提高分泌和增加的磺酰胺酶激活协同作用，以增强酶的生物分布。将这种基因传递策略翻译为MPS-IIIA小鼠模型可挽救包括记忆缺陷在内的脑部病理，并改善体细胞组织。这些数据可能为开发有效的基因递送替代方案治疗MPS-IIIA患者铺平道路。