Nebulized and intravenous enzyme replacement therapy in mice with mucopolysaccharidosis type II

Alex J. Shamoun, Gisienne Reis, Malaica Ashley, Anatalia Labilloy, Leonardo F. Ferreira
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Abstract

Mucopolysaccharidosis Type II is a hereditary lysosomal storage disease characterized by deficiency in the enzyme iduronate 2-sulfatase (IDS). IDS is critical in the breakdown of sulfated glycosaminoglycans and its deficiency leads to an accumulation of these compounds across various tissue types resulting in multisystemic dysfunction. Intravenous administration of recombinant IDS (idursulfase) substantially improves patients’ quality and length of life. However, recombinant IDS delivered intravenously is sequestered in the liver and respiratory failure remains as the leading cause of death for patients independent of idursulfase treatment, which suggests insufficient delivery to the lungs. This study aimed to assess a novel method of idursulfase administration using a nebulizer in combination with intravenous treatment and determine if this combination may improve lung delivery of idursulfase and overall pathology. Whole body IDS knockout mice underwent twelve weeks of intravenous, combination treatment, or vehicle injection and we harvested liver and lungs seven days after the last treatment for assessment of IDS activity, histological markers, and global proteomics for comparison with wild-type mice. Combination treatment increased IDS enzyme activity in the liver but not lungs Proteomics data demonstrated attenuation of key features of the disease in liver (metabolic pathways) and lungs (glycosaminoglycan pathways) with both treatments. Overall, adding nebulized administration of IDS did not lead to sustained increase in enzyme activity in the lungs but caused persistent modifications in glycosaminoglycan degradation pathway suggesting additional benefits to intravenous administration alone.
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黏多醣症II型小鼠的雾化和静脉注射酶替代疗法
粘多糖病 II 型是一种遗传性溶酶体贮积病,其特征是缺乏胰蛋白酶 2-硫酸酯酶(IDS)。IDS 在硫酸化糖胺聚糖的分解过程中起着关键作用,它的缺乏会导致这些化合物在各种组织类型中积聚,造成多系统功能障碍。静脉注射重组 IDS(idursulfase)可大大改善患者的生活质量和寿命。然而,静脉注射重组 IDS 会在肝脏中螯合,呼吸衰竭仍然是导致患者死亡的主要原因,而与 idursulfase 治疗无关,这表明向肺部的输送不足。本研究旨在评估使用雾化器结合静脉治疗给药伊豆磺酸酶的新方法,并确定这种组合是否能改善伊豆磺酸酶的肺部给药和整体病理学。全身 IDS 基因敲除小鼠接受了 12 周的静脉注射、联合治疗或载体注射,我们在最后一次治疗七天后收获了肝脏和肺脏,以评估 IDS 活性、组织学标记物和全局蛋白质组学,并与野生型小鼠进行比较。联合治疗可增加肝脏中的 IDS 酶活性,但不能增加肺脏中的 IDS 酶活性 蛋白质组学数据显示,两种治疗方法都可减轻肝脏(代谢途径)和肺脏(糖胺聚糖途径)中疾病的关键特征。总体而言,雾化吸入 IDS 不会导致肺部酶活性的持续增加,但会引起糖胺聚糖降解途径的持续改变,这表明雾化吸入 IDS 比单独静脉注射 IDS 有更多益处。
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