更新于：2024-09-19

HEXB

更新于：2024-09-19

基本信息

别名

Beta-hexosaminidase subunit beta、Beta-hexosaminidase subunit beta chain A、Beta-hexosaminidase subunit beta chain B

+ [7]

简介

Hydrolyzes the non-reducing end N-acetyl-D-hexosamine and/or sulfated N-acetyl-D-hexosamine of glycoconjugates, such as the oligosaccharide moieties from proteins and neutral glycolipids, or from certain mucopolysaccharides (PubMed:11707436, PubMed:9694901, PubMed:8672428, PubMed:8123671). The isozyme B does not hydrolyze each of these substrates, however hydrolyzes efficiently neutral oligosaccharide (PubMed:11707436). Only the isozyme A is responsible for the degradation of GM2 gangliosides in the presence of GM2A (PubMed:9694901, PubMed:8672428, PubMed:8123671). During fertilization is responsible, at least in part, for the zona block to polyspermy. Present in the cortical granules of non-activated oocytes, is exocytosed during the cortical reaction in response to oocyte activation and inactivates the sperm galactosyltransferase-binding site, accounting for the block in sperm binding to the zona pellucida (By similarity).

关联

靶点

HEXA x HEXB

作用机制

HEXA调节剂 [+2]

在研机构

Autonomous University of Barcelona

原研机构

Autonomous University of Barcelona

在研适应症

山德霍夫病 [+1]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

AAV9-HEXA/HEXB gene therapy (Axovant Sciences)

靶点

HEXA x HEXB

作用机制

HEXA调节剂 [+2]

在研机构

UMass Chan Medical School [+1]

原研机构

UMass Chan Medical School

在研适应症

泰-萨克斯病 [+1]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

TSHA-101

靶点

HEXA x HEXB

作用机制

HEXA调节剂 [+1]

在研机构-

原研机构

The University of Texas Southwestern Medical Center

在研适应症-

非在研适应症

GM2神经节苷脂贮积症

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

项与 HEXB 相关的临床试验

NCT04798235 / Active, not recruiting临床1/2期IIT

Phase 1/2, Open-Label Clinical Study to Evaluate the Safety and Efficacy of Intrathecal TSHA-101 Gene Therapy for Treatment of Infantile Onset GM2 Gangliosidosis

GM2 gangliosidoses are a group of autosomal recessive neurodegenerative diseases characterized by a deficiency of the Hex A enzyme to catabolize GM2, thereby causing GM2 accumulation within cellular lysosomes.Hex A is composed of 2 subunits, α- and β-, coded by the HEXA and HEXB genes, respectively. The primary purpose of the current study is to assess the safety and tolerability of TSHA101 administered via IT injection.

开始日期2021-03-12

申办/合作机构

Queen's University

[+2]

100 项与 HEXB 相关的临床结果

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100 项与 HEXB 相关的转化医学

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0 项与 HEXB 相关的专利（医药）

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621

项与 HEXB 相关的文献（医药）

2024-11-01·Current Molecular Medicine

Targeting GM2 Ganglioside Accumulation in Dementia: Current Therapeutic Approaches and Future Directions

Article

作者: Panda, Siva Prasad ; Kumar, Sanjesh

Abstract:Dementia in neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia with Lewy bodies (DLB) is a progressive neurological condition affecting millions worldwide. The amphiphilic molecule GM2 gangliosides are abundant in the human brain and play important roles in neuronal development, intercellular recognition, myelin stabilization, and signal transduction. GM2 ganglioside’s degradation requires hexosaminidase A (HexA), a heterodimer composed of an α subunit encoded by HEXA and a β subunit encoded by HEXB. The hydrolysis of GM2 also requires a non-enzymatic protein, the GM2 activator protein (GM2-AP), encoded by GM2A. Pathogenic mutations of HEXA, HEXB, and GM2A are responsible for autosomal recessive diseases known as GM2 gangliosidosis, caused by the excessive intralysosomal accumulation of GM2 gangliosides. In AD, PD and DLB, GM2 ganglioside accumulation is reported to facilitate Aβ and α-synuclein aggregation into toxic oligomers and plaques through activation of downstream signaling pathways, such as protein kinase C (PKC) and oxidative stress factors. This review explored the potential role of GM2 ganglioside alteration in toxic protein aggregations and its related signaling pathways leading to neurodegenerative diseases. Further review explored potential therapeutic approaches, which include synthetic and phytomolecules targeting GM2 ganglioside accumulation in the brain, holding a promise for providing new and effective management for dementia.

2024-09-01·Molecular Therapy - Methods & Clinical Development

Treating late-onset Tay Sachs disease: Brain delivery with a dual trojan horse protein

Article

作者: Kohen, Fortune ; Shenberger, Yulia ; Osher, Esther ; Singer-Shapiro, Ruth ; Fattal-Valevski, Aviva ; Urshanski, Nataly ; Weitman, Michal ; Sagi, Liora ; Valevski, Avi ; Weisinger, Gary ; Sagiv, Nadav ; Bogin, Oren ; Navon, Ruth ; Stern, Naftali ; Wilchek, Meir ; Anis, Yossi ; Albeck, Shira ; Unger, Tamar

Tay-Sachs (TS) disease is a neurodegenerative disease resulting from mutations in the gene encoding the α-subunit (HEXA) of lysosomal β-hexosaminidase A (HexA). We report that (1) recombinant HEXA alone increased HexA activity and decreased GM2 content in human TS glial cells and peripheral mononuclear blood cells; 2) a recombinant chimeric protein composed of HEXA linked to two blood-brain barrier (BBB) entry elements, a transferrin receptor binding sequence and granulocyte-colony stimulating factor, associates with HEXB in vitro; reaches human cultured TS cells lysosomes and mouse brain cells, especially neurons, in vivo; lowers GM2 in cultured human TS cells; lowers whole brain GM2 concentration by approximately 40% within 6 weeks, when injected intravenously (IV) to adult TS-mutant mice mimicking the slow course of late-onset TS; and increases forelimbs grip strength. Hence, a chimeric protein equipped with dual BBB entry elements can transport a large protein such as HEXA to the brain, decrease the accumulation of GM2, and improve muscle strength, thereby providing potential treatment for late-onset TS.

2024-08-01·Molecular Genetics and Metabolism

Tandem mass spectrometric enzyme assay for simultaneous detection of Tay-Sachs and Sandhoff diseases in dried blood spots for newborn screening

Article

作者: Herbst, Zackary M ; Gelb, Michael H ; Khaledi, Hamid ; Hold, Stephan

GM2 gangliosidosis is a group of rare lysosomal storage disorders (LSDs) including Tay-Sachs disease (TSD) and Sandhoff disease (SD), caused by deficiency in activity of either β-hexosaminidase A (HexA) or both β-hexosaminidase A and β-hexosaminidase B (HexB). Methods for screening and diagnosis of TSD and SD include measurement and comparison of the activity of these two enzymes. Here we report a novel method for duplex screening of dried blood spots (DBS) for TSD and SD by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The method requires incubation of a single 3 mm DBS punch with the assay cocktail followed by the injection into the LC-MS/MS. The performance of the method was evaluated by comparing the confirmed TSD and SD patient DBS to random healthy newborn DBS which showed easy discrimination between the three cohorts. The method is multiplexable with other LSD MS/MS enzyme assays which is critical to the continued expansion of the NBS panels.

项与 HEXB 相关的新闻（医药）

2024-01-23

·生物探索

NCB | 浙江大学徐平龙/沈承勇/李欣然发现溶酶体功能障碍的先天免疫感应引发多种溶酶体贮积症

引言溶酶体贮积症(LSDs)是一种以遗传和代谢性溶酶体功能障碍为特征的60多种退行性疾病，具有相当大的健康和经济负担。然而，由于溶酶体缺陷导致功能细胞进行性死亡的机制仍然不完全清楚，并且缺乏针对LSDs的广谱治疗方法。2024年1月22日，浙江大学徐平龙、沈承勇及李欣然共同通讯在Nature Cell Biology 在线发表题为“Innate immune sensing of lysosomal dysfunction drives multiple lysosomal storage disorders”的研究论文，该研究发现导致LSDs的各种基因异常，包括Hexb、Gla、Npc1、Ctsd和Gba，都有共同的特性，可以强大地自激活神经元内在的cGAS-STING信号，驱动神经元死亡和疾病进展。这种信号是由神经元中dsDNA和DNA传感器cGAS的过度细胞质聚集引发的。基因消融cGAS或STING，用DNA酶消化神经元胞质dsDNA，修复神经元溶酶体功能障碍，可减轻Sandhoff病、Fabry病和niemmann-pick病的症状，显著减少神经元损失。因此，该研究确定了介导多种LSDs发病机制的普遍机制，揭示了溶酶体缺陷与先天免疫之间的内在联系，并提出了治疗LSDs的统一策略。LSDs是一组以溶酶体功能障碍为特征的60多种遗传和代谢性疾病。大多数LSDs是常染色体隐性突变和单基因突变，主要使溶酶体水解酶和转运蛋白失活，导致溶酶体和细胞质中各种物质积聚。LSDs在临床上是异质性的，四分之三的LSDs涉及中枢神经系统的神经元储存问题和随后的细胞死亡，导致大量的神经功能缺陷，如认知能力下降、共济失调、癫痫和智力残疾，以及肌肉、脾脏和骨骼的缺陷，以及生长迟缓。例如，逐渐破坏脑和脊髓神经元的Sandhoff病，是由Hexb基因突变和β-己糖氨酸酶A和B失活引起的，导致神经元中GM2神经节苷脂沉积，最终导致神经退行性变。Sandhoff病的早期发病会导致运动技能丧失，并导致癫痫发作、视力和听力丧失以及智力残疾；患有Sandhoff病的人通常活不过幼儿期。遗憾的是，到目前为止，还没有治愈Sandhoff病病的方法。目前，用于治疗LSDs的现有疗法，包括酶替代疗法(ERT)、底物还原疗法(SRT)和药理学伴侣，仅覆盖有限比例的疾病，成本非常高，反应性有限。基因组编辑为LSD治疗方案开辟了新的视野；然而，这种方法仍处于起步阶段，仅得到动物模型实验的支持。因此，迫切需要研究一种有效和普遍的治疗方法。神经元天生易受溶酶体储存的影响，因为这些终末分化的细胞不能通过细胞分裂稀释底物和受损的细胞器。主流观点认为，溶酶体损伤可引发细胞凋亡、坏死、焦亡、铁死亡等细胞死亡模式。溶酶体储存引起的应激还会诱导溶酶体膜通透性，并将溶酶体成分(如组织蛋白酶)释放到细胞质中，从而导致溶酶体细胞死亡，这可能导致一种称为Sjögren综合征的自身免疫性疾病的发生。脑外伤后神经元溶酶体膜通透性可导致自噬受损和神经元细胞死亡。内质网应激被认为是溶酶体贮积病中常见的细胞凋亡调节因子。然而，从溶酶体功能障碍到神经元死亡的确切体内途径尚不清楚。神经炎症是LSDs的常见病理特征，主要涉及行为表型前的小胶质细胞激活和星形胶质细胞增生。然而，各种LSDs中溶酶体功能障碍、免疫反应和神经元死亡之间的分子和细胞联系机制尚不清楚。模式图（Source: Nature Cell Biology ）该研究发现由于溶酶体附近胞质dsDNA和cGAS蛋白的异常积累，cGAS-STING信号在过多的LSDs中是组成性的和过度活跃的。LSDs中神经元内在cGAS-STING信号的异常激活导致神经元死亡、神经炎症和运动功能障碍。cGAS和STING都是体内疾病发生的必要条件。通过神经元DNA酶重组消化多余的细胞质dsDNA，大大减轻了这些疾病的表型。因此，该研究确定了cGAS-STING机制是溶酶体储存的关键传感器，并提出了各种LSDs发病机制中通用和可靶向的信号通路。原文链接：https://www-nature-com.libproxy1.nus.edu.sg/articles/s41556-023-01339-x 责编|探索君排版|探索君文章来源|“iNature”End往期精选围观王晓红教授团队：绘制单次冷冻囊胚移植成功的女性植入期外周血microRNA动态表达谱，开拓领域创新研究热文维生素B12在细胞重编程与组织再生中发挥关键作用！热文不孕症治疗新方向！又一导致女性不孕的关键因素被发现热文Let-7家族miRNA或为癌症潜在免疫治疗靶点热文一项最新发现或可用于阿尔茨海默病药物开发点击“阅读原文”，了解更多~