PDF(Pubmed)
Abstract：
Mucopolysaccharidoses (MPSs) are a group of inborn errors of the metabolism caused by a deficiency in the lysosomal enzymes required to break down molecules called glycosaminoglycans (GAGs). These GAGs accumulate over time in various tissues and disrupt multiple biological systems, including catabolism of other substances, autophagy, and mitochondrial function. These pathological changes ultimately increase oxidative stress and activate innate immunity and inflammation. We have described the pathophysiology of MPS and activated inflammation in this paper, starting with accumulating the primary storage materials, GAGs. At the initial stage of GAG accumulation, affected tissues/cells are reversibly affected but progress irreversibly to: (1) disruption of substrate degradation with pathogenic changes in lysosomal function, (2) cellular dysfunction, secondary/tertiary accumulation (toxins such as GM2 or GM3 ganglioside, etc.), and inflammatory process, and (3) progressive tissue/organ damage and cell death (e.g., skeletal dysplasia, CNS impairment, etc.). For current and future treatment, several potential treatments for MPS that can penetrate the blood-brain barrier and bone have been proposed and/or are in clinical trials, including targeting peptides and molecular Trojan horses such as monoclonal antibodies attached to enzymes via receptor-mediated transport. Gene therapy trials with AAV, ex vivo LV, and Sleeping Beauty transposon system for MPS are proposed and/or underway as innovative therapeutic options. In addition, possible immunomodulatory reagents that can suppress MPS symptoms have been summarized in this review.
摘要：
粘多糖糖（MPS）是一组先天性代谢错误，由分解称为糖胺聚糖（GAG）的分子所需的溶酶体酶缺乏引起。这些GAG随着时间的推移在各种组织中积累并破坏多个生物系统，包括其他物质的分解代谢，自噬,和线粒体功能。这些病理变化最终增加氧化应激并激活先天免疫和炎症。我们在本文中描述了MPS和活化炎症的病理生理学，从积累初级储存材料开始，GAG.在GAG积累的初始阶段，受影响的组织/细胞受到可逆的影响，但不可逆地进展到：（1）底物降解的破坏与溶酶体功能的致病性变化，(2)细胞功能障碍,二级/三级积累(毒素，如GM2或GM3神经节苷脂，等。),和炎症过程，和(3)进行性组织/器官损伤和细胞死亡(例如，骨骼发育不良,中枢神经系统损害，等。).对于当前和未来的治疗，已经提出了几种可以穿透血脑屏障和骨骼的MPS的潜在治疗方法和/或正在进行临床试验。包括靶向肽和分子特洛伊木马，例如通过受体介导的转运与酶连接的单克隆抗体。AAV基因治疗试验，离体LV,和MPS的睡美人转座子系统被提议和/或正在作为创新的治疗选择。此外,本文综述了可能抑制MPS症状的免疫调节试剂。
