Department of Pharmacology, Pharmacy and Pharmaceutical Technology, School of Pharmacy, Campus Vida, University of Santiago de Compostela, 15872 Santiago de Compostela, Spain.
Department of Forensic Sciences, Pathology, Gynecology and Obstetrics, Pediatrics, Neonatology Service, Department of Paediatrics, Hospital Clínico Universitario de Santiago de Compostela, Health Research Institute of Santiago de Compostela (IDIS), CIBERER, MetabERN, 15706 Santiago de Compostela, Spain.
Int J Mol Sci. 2019 Sep 18;20(18):4610. doi: 10.3390/ijms20184610.
Morquio A syndrome, or mucopolysaccharidosis type IVA (MPS IVA), is a lysosomal storage disease due to mutations in the N-acetylgalactosamine-6-sulfatase () gene. Systemic skeletal dysplasia and the related clinical features of MPS IVA are due to disruption of cartilage and its extracellular matrix, leading to an imbalance of growth. Enzyme replacement therapy (ERT) with recombinant human GALNS, alpha elosulfase, provides a systemic treatment. However, this therapy has a limited impact on skeletal dysplasia because the infused enzyme cannot penetrate cartilage and bone. Therefore, an alternative therapeutic approach to reach the cartilage is an unmet challenge. We have developed a new drug delivery system based on a nanostructure lipid carrier with the capacity to immobilize enzymes used for ERT and to target the lysosomes. This study aimed to assess the effect of the encapsulated enzyme in this new delivery system, using in vitro proteomic technology. We found a greater internalization of the enzyme carried by nanoparticles inside the cells and an improvement of cellular protein routes previously impaired by the disease, compared with conventional ERT. This is the first qualitative and quantitative proteomic assay that demonstrates the advantages of a new delivery system to improve the MPS IVA ERT.
黏多糖贮积症 A 型（Mucopolysaccharidosis type IVA，MPS IVA），又称莫尔奎奥综合征，是一种由于 N-乙酰半乳糖胺-6-硫酸酯酶（N-acetylgalactosamine-6-sulfatase，GALNS）基因突变导致的溶酶体贮积症。全身性骨骼发育不良以及 MPS IVA 的相关临床特征是由于软骨及其细胞外基质受到破坏，导致生长失衡。重组人 GALNS（alpha elosulfase）的酶替代疗法（Enzyme replacement therapy，ERT）为全身性治疗方法。然而，这种治疗方法对骨骼发育不良的影响有限，因为输注的酶无法穿透软骨和骨骼。因此，一种替代的治疗方法来到达软骨是一个尚未满足的挑战。我们开发了一种基于纳米结构脂质载体的新型药物递送系统，该系统能够固定用于 ERT 的酶，并靶向溶酶体。本研究旨在使用体外蛋白质组学技术评估该新型递送系统中包封酶的效果。与传统的 ERT 相比，我们发现纳米颗粒内携带的酶在细胞内有更高的内化率，并改善了先前被疾病损害的细胞内蛋白质途径。这是第一个定性和定量蛋白质组学分析，证明了一种新的递送系统在改善 MPS IVA ERT 方面的优势。
