GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies.
GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies.
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DOI：
10.3390/ijms21176213
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发表时间：
2020-08-27
影响因子：
5.6
通讯作者：
Espejo-Mojica AJ
中科院分区：
文献类型：
--
作者：
Leal AF;Benincore-Flórez E;Solano-Galarza D;Garzón Jaramillo RG;Echeverri-Peña OY;Suarez DA;Alméciga-Díaz CJ;Espejo-Mojica AJ
GM2神经节苷脂剂量是由于编码β-己糖氨酸酶亚基或GM2激活蛋白的基因突变而导致GM2神经节苷脂积累到溶酶体中的一组病理。已经描述了三种GM2神经节脂质剂量：Tay-Sachs病、Sandhoff病和AB变体。中枢神经系统功能障碍是GM2神经节脂质剂量患者的主要特征，包括神经发育改变、神经炎症和神经元凋亡。目前，尚无批准的GM2神经节脂苷剂量治疗方法，但研究了不同的治疗策略，包括造血干细胞移植、酶替代治疗、底物减少治疗、药物伴侣和基因治疗。血脑屏障对开发治疗这些疾病的药物是一个挑战。从这个意义上说，已经评估了其他给药途径（例如，鞘内或脑室内），以及融合肽的设计，使蛋白质能够从脑毛细血管运输到中枢神经系统。在这篇综述中，我们概述了目前关于GM2神经节苷脂剂量的临床和生理病理发现的知识，以及通过使用分子特洛伊木马或先进的基因组编辑工具等新策略来克服传统替代品的一些局限性的建议。
GM2 gangliosidoses are a group of pathologies characterized by GM2 ganglioside accumulation into the lysosome due to mutations on the genes encoding for the β-hexosaminidases subunits or the GM2 activator protein. Three GM2 gangliosidoses have been described: Tay–Sachs disease, Sandhoff disease, and the AB variant. Central nervous system dysfunction is the main characteristic of GM2 gangliosidoses patients that include neurodevelopment alterations, neuroinflammation, and neuronal apoptosis. Currently, there is not approved therapy for GM2 gangliosidoses, but different therapeutic strategies have been studied including hematopoietic stem cell transplantation, enzyme replacement therapy, substrate reduction therapy, pharmacological chaperones, and gene therapy. The blood–brain barrier represents a challenge for the development of therapeutic agents for these disorders. In this sense, alternative routes of administration (e.g., intrathecal or intracerebroventricular) have been evaluated, as well as the design of fusion peptides that allow the protein transport from the brain capillaries to the central nervous system. In this review, we outline the current knowledge about clinical and physiopathological findings of GM2 gangliosidoses, as well as the ongoing proposals to overcome some limitations of the traditional alternatives by using novel strategies such as molecular Trojan horses or advanced tools of genome editing.
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作者：
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通讯作者：
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