更新于：2024-05-01

AGL

amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase

更新于：2024-05-01

基本信息

别名

4-alpha-glucanotransferase、AGL、Amylo-1,6-glucosidase

+ [7]

简介

Multifunctional enzyme acting as 1,4-alpha-D-glucan:1,4-alpha-D-glucan 4-alpha-D-glycosyltransferase and amylo-1,6-glucosidase in glycogen degradation.

关联

项与 AGL 相关的药物

UX-053

靶点

AGL

作用机制

AGL调节剂

在研机构

Arcturus Therapeutics Holdings, Inc.

原研机构

Arcturus Therapeutics Holdings, Inc.

在研适应症

糖原贮积病

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

AAV based gene therapy (Genethon)

靶点

AGL

作用机制

AGL调节剂

在研机构-

原研机构

Genethon

在研适应症-

非在研适应症

糖原贮积病Ⅲ型

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

项与 AGL 相关的临床试验

EUCTR2021-000903-19-IT / Unknown status临床1/2期

A Phase 1/2 First-in-human, 2-part Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single Ascending Doses (Part 1: Open-label) and Repeat Doses (Part 2: Randomized, Double-blind, Placebo-controlled) of UX053 in Patients with GSD III - UX053-CL101

开始日期-

申办/合作机构

Ultragenyx Pharmaceutical, Inc.

EUCTR2021-000903-19-ES / Unknown status临床1/2期

开始日期2021-11-26

申办/合作机构

Ultragenyx Pharmaceutical, Inc.

NCT04990388 / Terminated临床1/2期

A Phase 1/2 First-in-human, Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single Ascending Doses and Repeat Doses of UX053 in Patients With GSD III

The primary objective of the study is to evaluate the safety of UX053 in adults with Glycogen Storage Disease Type III (GSD III).

开始日期2021-10-18

申办/合作机构

Ultragenyx Pharmaceutical, Inc.

100 项与 AGL 相关的临床结果

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100 项与 AGL 相关的转化医学

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0 项与 AGL 相关的专利（医药）

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411

项与 AGL 相关的文献（医药）

2024-02-06·The Science of the total environment

Surface coating combined with in situ cyclic voltammetry to enhance the stability of gas diffusion electrodes for electrochemical CO₂ reduction.

Article

作者: Ying Pu ; Gaoying Wu ; Yue Wang ; Xiaobing Wu ; Na Chu ; Raymond Jianxiong Zeng ; Yong Jiang

Electrochemical CO₂ reduction (CO₂RR), fueled by clean and renewable energy, presents a promising method for utilizing CO₂ effectively. The electrocatalytic reduction of CO₂ to CO using a gas diffusion electrode (GDE) has shown great potential for industrial applications due to its high reaction rate and selectivity. However, guaranteeing its long-term stability still poses a significant challenge. In this study, we conducted a comprehensive investigation into various strategies to enhance the stability of the GDE. These strategies involved modifying the structure of the substrate, such as the gas diffusion layer (GDL) and the back side of the GDL (macroporous layer side). Additionally, we explored modifications to the catalyst layer (CL) and the front of the CL. To address these stability concerns, we proposed a practical approach that involved surface coating using carbon black in combination with in situ cyclic voltammetry (CV) cycles on Ag/Ag₃₀₀/polytetrafluoroethylene (PTFE). The partial Faradaic efficiency exceeded 80 % within a span of 70 h. Electron microscopy and electrochemical characterization revealed that the implementation of in situ CV led to a reduction in catalyst particle size and the formation of a porous surface structure. By enhancing the stability of the GDE, this research opens up possibilities for the advancement of hybrid systems that focus on the production and utilization of syngas.

2024-01-01·PloS one

A novel genetic model provides a unique perspective on the relationship between postexercise glycogen concentration and increases in the abundance of key metabolic proteins after acute exercise.

Article

作者: Seong Eun Kwak ; Amy Zheng ; Edward B Arias ; Haiyan Wang ; Xiufang Pan ; Yongping Yue ; Dongsheng Duan ; Gregory D Cartee

Some acute exercise effects are influenced by postexercise (PEX) diet, and these diet-effects are attributed to differential glycogen resynthesis. However, this idea is challenging to test rigorously. Therefore, we devised a novel genetic model to modify muscle glycogen synthase 1 (GS1) expression in rat skeletal muscle with an adeno-associated virus (AAV) short hairpin RNA knockdown vector targeting GS1 (shRNA-GS1). Contralateral muscles were injected with scrambled shRNA (shRNA-Scr). Muscles from exercised (2-hour-swim) and time-matched sedentary (Sed) rats were collected immediately postexercise (IPEX), 5-hours-PEX (5hPEX), or 9-hours-PEX (9hPEX). Rats in 5hPEX and 9hPEX experiments were refed (RF) or not-refed (NRF) chow. Muscles were analyzed for glycogen, abundance of metabolic proteins (pyruvate dehydrogenase kinase 4, PDK4; peroxisome proliferator-activated receptor γ coactivator-1α, PGC1α; hexokinase II, HKII; glucose transporter 4, GLUT4), AMP-activated protein kinase phosphorylation (pAMPK), and glycogen metabolism-related enzymes (glycogen phosphorylase, PYGM; glycogen debranching enzyme, AGL; glycogen branching enzyme, GBE1). shRNA-GS1 versus paired shRNA-Scr muscles had markedly lower GS1 abundance. IPEX versus Sed rats had lower glycogen and greater pAMPK, and neither of these IPEX-values differed for shRNA-GS1 versus paired shRNA-Scr muscles. IPEX versus Sed groups did not differ for abundance of metabolic proteins, regardless of GS1 knockdown. Glycogen in RF-rats was lower for shRNA-GS1 versus paired shRNA-Scr muscles at both 5hPEX and 9hPEX. HKII protein abundance was greater for 5hPEX versus Sed groups, regardless of GS1 knockdown or diet, and despite differing glycogen levels. At 9hPEX, shRNA-GS1 versus paired shRNA-Scr muscles had greater PDK4 and PGC1α abundance within each diet group. However, the magnitude of PDK4 or PGC1α changes was similar in each diet group regardless of GS1 knockdown although glycogen differed between paired muscles only in RF-rats. In summary, we established a novel genetic approach to investigate the relationship between muscle glycogen and other exercise effects. Our results suggest that exercise-effects on abundance of several metabolic proteins did not uniformly correspond to differences in postexercise glycogen.

2023-11-28·The Journal of clinical investigation

A functional mini-GDE transgene corrects impairment in models of glycogen storage disease type III.

Article

作者: Antoine Gardin ; Jérémy Rouillon ; Valle Montalvo-Romeral ; Lucille Rossiaud ; Patrice Vidal ; Romain Launay ; Mallaury Vie ; Youssef Krimi Benchekroun ; Jérémie Cosette ; Bérangère Bertin ; Tiziana La Bella ; Guillaume Dubreuil ; Justine Nozi ; Louisa Jauze ; Romain Fragnoud ; Nathalie F Daniele ; Laetitia Van Wittenberghe ; Jérémy Esque ; Isabelle André ; Xavier Nissan ; Lucile Hoch ; Giuseppe Ronzitti

Glycogen storage disease type III (GSDIII) is a rare inborn error of metabolism affecting liver, skeletal muscle, and heart due to mutations of the AGL gene encoding for the glycogen debranching enzyme (GDE). No curative treatment exists for GSDIII. The 4.6 kb GDE cDNA represents the major technical challenge toward the development of a single recombinant adeno-associated virus (rAAV)-derived vector gene therapy strategy. Using information on GDE structure and molecular modeling, we generated multiple truncated GDEs retaining activity. Among them, an N-terminal-truncated mutant ∆Nter2-GDE had a similar efficacy in vivo compared to the full-size enzyme. A rAAV vector expressing ∆Nter2-GDE allowed significant glycogen reduction in heart and muscle of Agl-/- mice three months after intravenous injection, as well as normalization of histology features and restoration of muscle strength. Similarly, glycogen accumulation and histological features were corrected in a recently generated Agl-/- rat model. Finally, transduction with rAAV vectors encoding ∆Nter2-GDE corrected glycogen accumulation in an in vitro human skeletal muscle cellular model of GSDIII. In conclusion, our results demonstrated the ability of a single rAAV vector expressing a functional mini-GDE transgene to correct the muscle and heart phenotype in multiple models of GSDIII, supporting its clinical translation to GSDIII patients.

项与 AGL 相关的新闻（医药）

2023-03-12

·药明康德

前沿 | 100%存活率！这类创新mRNA疫苗让小鼠体内的肿瘤消失了

▎药明康德内容团队编辑HPV疫苗可以有效预防绝大多数与HPV（人类乳头瘤病毒）感染相关的癌症，比如头颈癌、肛门癌、阴茎癌和宫颈癌，但它只对提前注射疫苗的人有效果，而上述癌症的既有患者在依赖现有疗法的同时，恐怕只能寄希望于治疗性疫苗的研发。最近，发表在《科学》杂志子刊Science Translational Medicine上的一项研究结果似乎预示着这种治疗性的疫苗有望成为现实。巴西圣保罗大学（University of São Paulo）和宾夕法尼亚大学（University of Pennsylvania）的研究人员研制了三种mRNA疫苗并在小鼠身上进行了测试，这些疫苗旨在增强免疫系统，使其攻击由HPV感染所产生的癌细胞。实验表明，三种mRNA疫苗中的任何一种都能够清除小鼠的肿瘤，在实验结束前，绝大多数小鼠保持着无癌症的状态。这不是科学家们第一次尝试研发对抗HPV相关癌症的疫苗。在2021年，BioNTech公司和赛诺菲（Sanofi）便合作开发了一种mRNA疫苗，显著缩小肿瘤并且延长了小鼠的生存期。BioNTech公司目前正在进行2期临床试验，以测试旗下治疗性mRNA疫苗BNT113与帕博利珠单抗联合治疗HPV16阳性的头颈部鳞状细胞癌的效果。BNT113是一款编码HPV16致癌蛋白E6和E7的治疗性mRNA疫苗，通过激发机体针对HPV16蛋白的免疫反应来发挥抗癌效果。在这篇文章中，研究人员测试的三种疫苗都使用了可编码产生gDE7蛋白组分的mRNA分子。gDE7蛋白是一种融合蛋白，由两种不同的蛋白质融合产生，其第一种组分蛋白是gD，它来自疱疹病毒，可以增强机体对第二种蛋白组分——HPV病毒E7蛋白的免疫反应。当HPV感染宿主后，病毒的E7和E6的蛋白可以破坏关键抑癌基因的功能，帮助病毒将正常细胞转化为癌细胞。对于疫苗的靶点选择，研究人员指出，由于E6/E7蛋白是HPV相关癌症所必需的，所以它们是非常好的靶点，这也意味着这类癌症的癌细胞应该更难对靶向E6或E7的mRNA疫苗产生耐药性。图片来源：123RF研究人员选择了脂质纳米颗粒（LNP）作为mRNA疫苗递送的载体。当这些脂质颗粒将mRNA传递给细胞，并在细胞内表达产生gDE7蛋白后，细胞会将这些蛋白切碎成抗原，并将其呈递给免疫系统，以产生响应的抗体和白细胞。至此，这些免疫细胞的效应分子和效应细胞将开始追捕并摧毁体内含有这些抗原的癌细胞。在这篇研究中，研究人员测试的三种mRNA疫苗在技术上略有不同。其中一种通过修饰碱基对的方式来增加疫苗产生的蛋白量，另一种使用了一种叫做自扩增RNA（self-amplifying RNA）的技术来提高蛋白产量，第三种疫苗则不对mRNA进行任何二次修饰。研究人员想通过比较三种不同的RNA修饰策略，测试在编码相同抗原的情况下，基于不同修饰策略的mRNA疫苗在体内实验中的表现。科学家们首先将HPV相关肿瘤移植到小鼠体内，然后，这些小鼠分别接种三种mRNA疫苗中的任意一种。三个月后，一些老鼠被移植了另一个肿瘤。实验结束时，研究人员发现，所有接种了修饰碱基对的mRNA疫苗或经过自扩增RNA技术修饰的疫苗的小鼠都存活到了研究结束，80%接种了未经修饰的mRNA疫苗的小鼠存活了下来，接受DNA或蛋白疫苗的小鼠都没有在第二次肿瘤植入中存活下来。图片来源：123RF此外，研究人员还发现，mRNA疫苗能够诱导高水平的T细胞，这些T细胞能够识别HPV的E7蛋白并摧毁携带该蛋白的癌细胞。研究人员指出，这些T细胞仍可能造成实验中再次植入肿瘤的小鼠的癌症消退，这表明mRNA疫苗能够产生针对癌症的免疫记忆。该团队表示，他们的下一步计划是将这些疫苗推进至人体试验阶段。人类和小鼠的体内环境存在很大的区别，因此任何技术或疗法最终都需要在人类身上进行概念验证，这是判断它们是否能在临床上推进的关键依据。研究人员对于这一计划持谨慎且乐观态度，他们认为这些mRNA疫苗在本研究中展示出的免疫原性和治疗效果数据足以支持它们的临床研究。药明康德为全球生物医药行业提供一体化、端到端的新药研发和生产服务，服务范围涵盖化学药研发和生产、生物学研究、临床前测试和临床试验研发、细胞及基因疗法研发、测试和生产等领域。如您有相关业务需求，欢迎点击下方图片填写具体信息。▲如您有任何业务需求，请长按扫描上方二维码，或点击文末“阅读原文/Read more”，即可访问业务对接平台，填写业务需求信息▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料：[1] Ramos da Silva, Jamile et al. “Single immunizations of self-amplifying or non-replicating mRNA-LNP vaccines control HPV-associated tumors in mice.” Science translational medicine vol. 15,686 (2023): eabn3464. doi:10.1126/scitranslmed.abn3464[2] An mRNA vaccine for cancers associated with HPV shows promise in mice，Retrieved March 10th, 2023, from https://www.statnews.com/2023/03/03/mrna-vaccine-hpv-cancer/免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

疫苗信使RNA临床1期临床2期