更新于：2024-11-01

VAMP1

更新于：2024-11-01

基本信息

别名

泡囊相关膜蛋白1、SYB1、synaptobrevin 1

+ [5]

简介

Involved in the targeting and/or fusion of transport vesicles to their target membrane.

关联

项与 VAMP1 相关的药物

Botulinum Toxin Type B

靶点

VAMP1 x VAMP2

作用机制

VAMP1抑制剂 [+1]

在研机构

Supernus Pharmaceuticals, Inc. [+4]

原研机构

MDD US Operations LLC

在研适应症

流涎 [+10]

非在研适应症

先天性斜颈 [+1]

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2000-12-08

Ad5f35-LMPd1-2-transduced autologous dendritic cells(National Cancer Institute)

靶点

VAMP1 x VAMP2

作用机制

VAMP1调节剂 [+1]

在研机构-

原研机构

National Cancer Institute

在研适应症-

非在研适应症

鼻咽肿瘤

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 VAMP1 相关的临床试验

NCT04815967 / Active, not recruiting临床2/3期

Phase 2/3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Single-Treatment Efficacy and Safety Study of MYOBLOC in Treatment of Adult Upper Limb Spasticity and Open-Label Extension, Multiple-Treatment Safety Study of MYOBLOC

Phase 2/3, randomized, double-blind, placebo-controlled, single-treatment, multicenter trial assessing the efficacy and safety of MYOBLOC for the treatment of upper limb spasticity in adults followed by an open-label extension safety trial.

开始日期2021-11-16

申办/合作机构

Supernus Pharmaceuticals, Inc.

[+1]

NCT05097079 / Withdrawn临床3期

A Phase 3 Multicenter, Randomized, Double-Blind, Placebo-Controlled, Single-Treatment Efficacy and Safety Study of MYOBLOC® for the Treatment of Chronic Sialorrhea in Pediatric Subjects

This study will evaluate the efficacy and safety of MYOBLOC for the treatment of chronic sialorrhea in pediatric subjects.

开始日期2021-11-01

申办/合作机构-

EUCTR2020-005553-24-HU / Unknown status临床2/3期

A Phase 2/3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Single-Treatment Efficacy and Safety Study of MYOBLOC® in the Treatment of Adult Upper Limb Spasticity Followed by an Open-Label Extension, Multiple-Treatment Safety Study of MYOBLOC®

开始日期2021-07-07

申办/合作机构-

100 项与 VAMP1 相关的临床结果

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100 项与 VAMP1 相关的转化医学

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0 项与 VAMP1 相关的专利（医药）

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261

项与 VAMP1 相关的文献（医药）

2024-08-01·Pediatric Neurology

Advancing the Understanding of Vesicle-Associated Membrane Protein 1-Related Congenital Myasthenic Syndrome: Phenotypic Insights, Favorable Response to 3,4-Diaminopyridine, and Clinical Characterization of Five New Cases

Article

作者: Engel, Andrew G ; Jou, Cristina ; Estévez-Arias, Berta ; Tournev, Ivailo ; Lochmüller, Hanns ; Selcen, Duygu ; Thompson, Rachel ; Polavarapu, Kiran ; Todorova, Albena ; Shen, Xinming ; Pugliese, Alessia ; Guergueltcheva, Velina ; Matalonga, Leslie ; Afonso Ribeiro, Joana ; Lau, Jarred ; Natera-de Benito, Daniel ; Nascimento, Andres ; Ortez, Carlos ; Martorell, Loreto ; Laurie, Steven ; Fernández-Mayoralas, Daniel M

BACKGROUNDCongenital myasthenic syndromes (CMS) are a group of inherited neuromuscular junction (NMJ) disorders arising from gene variants encoding diverse NMJ proteins. Recently, the VAMP1 gene, responsible for encoding the vesicle-associated membrane protein 1 (VAMP1), has been associated with CMS.METHODSThis study presents a characterization of five new individuals with VAMP1-related CMS, providing insights into the phenotype.RESULTSThe individuals with VAMP1-related CMS exhibited early disease onset, presenting symptoms prenatally or during the neonatal period, alongside severe respiratory involvement and feeding difficulties. Generalized weakness at birth was a common feature, and none of the individuals achieved independent walking ability. Notably, all cases exhibited scoliosis. The clinical course remained stable, without typical exacerbations seen in other CMS types. The response to anticholinesterase inhibitors and salbutamol was only partial, but the addition of 3,4-diaminopyridine (3,4-DAP) led to significant and substantial improvements, suggesting therapeutic benefits of 3,4-DAP for managing VAMP1-related CMS symptoms. Noteworthy is the identification of the VAMP1 (NM_014231.5): c.340delA; p.Ile114SerfsTer72 as a founder variant in the Iberian Peninsula and Latin America.CONCLUSIONSThis study contributes valuable insights into VAMP1-related CMS, emphasizing their early onset, arthrogryposis, facial and generalized weakness, respiratory involvement, and feeding difficulties. Furthermore, the potential efficacy of 3,4-DAP as a useful therapeutic option warrants further exploration. The findings have implications for clinical management and genetic counseling in affected individuals. Additional research is necessary to elucidate the long-term outcomes of VAMP1-related CMS.

2024-06-01·Neuropediatrics

VAMP1-Related Congenital Myasthenic Syndrome: A Case Report and Literature Review

Review

作者: Yıldırım, Miraç ; Yarenci, Gülçin Bilicen ; Bektaş, Ömer ; Uçar, Çiğdem İlter ; Tekin, Merve Nur ; Genç, Mustafa Berk ; Teber, Serap ; Bayav, Secahattin

AbstractCongenital myasthenic syndrome-25 (CMS-25) is an autosomal recessive neuromuscular disorder caused by a homozygous mutation in VAMP1 gene. To date, only eight types of allelic variants in VAMP1 gene have been reported in 12 cases of CMS-25. Here, we report on an 8-year-old boy with motor developmental delay, axial hypotonia, myopathic face, muscle weakness, strabismus, ptosis, pectus carinatum, kyphoscoliosis, joint contractures, joint laxity, seizures, and recurrent nephrolithiasis. He also had feeding difficulties and recurrent aspiration pneumonia. Brain magnetic resonance imaging at 20 months of age showed left focal cerebellar hypoplasia. Genetic analysis revealed a homozygous missense variant of c.202C > T (p.Arg68Ter) in the VAMP1 gene. Treatment with oral pyridostigmine was started, which resulted in mild improvement in muscle strength. Salbutamol syrup was added a few months later, but no significant improvement was observed. This case report presents novel findings such as focal cerebellar hypoplasia and nephrolithiasis in VAMP1-related CMS-25. Consequently, this case report extends the clinical spectrum. Further studies are needed to expand the genotype–phenotype correlations in VAMP1-related CMS-25.

2024-05-01·Molecular Psychiatry

Altered Rbfox1-Vamp1 pathway and prefrontal cortical dysfunction in schizophrenia

Article

作者: Dienel, Samuel J ; Chung, Daniel W ; Ermentrout, G Bard ; Chung, Youjin ; Belch, Matthew J ; Fish, Kenneth N ; Lewis, David A

Deficient gamma oscillations in prefrontal cortex (PFC) of individuals with schizophrenia appear to involve impaired inhibitory drive from parvalbumin-expressing interneurons (PVIs). Inhibitory drive from PVIs is regulated, in part, by RNA binding fox-1 homolog 1 (Rbfox1). Rbfox1 is spliced into nuclear or cytoplasmic isoforms, which regulate alternative splicing or stability of their target transcripts, respectively. One major target of cytoplasmic Rbfox1 is vesicle associated membrane protein 1 (Vamp1). Vamp1 mediates GABA release probability from PVIs, and the loss of Rbfox1 reduces Vamp1 levels which in turn impairs cortical inhibition. In this study, we investigated if the Rbfox1-Vamp1 pathway is altered in PVIs in PFC of individuals with schizophrenia by utilizing a novel strategy that combines multi-label in situ hybridization and immunohistochemistry. In the PFC of 20 matched pairs of schizophrenia and comparison subjects, cytoplasmic Rbfox1 protein levels were significantly lower in PVIs in schizophrenia and this deficit was not attributable to potential methodological confounds or schizophrenia-associated co-occurring factors. In a subset of this cohort, Vamp1 mRNA levels in PVIs were also significantly lower in schizophrenia and were predicted by lower cytoplasmic Rbfox1 protein levels across individual PVIs. To investigate the functional impact of Rbfox1-Vamp1 alterations in schizophrenia, we simulated the effect of lower GABA release probability from PVIs on gamma power in a computational model network of pyramidal neurons and PVIs. Our simulations showed that lower GABA release probability reduces gamma power by disrupting network synchrony while minimally affecting network activity. Finally, lower GABA release probability synergistically interacted with lower strength of inhibition from PVIs in schizophrenia to reduce gamma power non-linearly. Together, our findings suggest that the Rbfox1-Vamp1 pathway in PVIs is impaired in schizophrenia and that this alteration likely contributes to deficient PFC gamma power in the illness.

项与 VAMP1 相关的新闻（医药）

2022-07-04

·生物制品圈

基于进化重编程的神经毒素蛋白酶设计

蛋白酶高效和特异性切割蛋白质靶标的能力使其能够在生物学、生物技术和医学中发挥重要作用。虽然目前蛋白酶经过改造或进化可以提高稳定性、溶剂耐受性、抑制剂抗性、活性和改变的特异性，但成功改变底物特异性超过一级肽识别序列中单个氨基酸的报道很少见。如果通过重编程以选择性地切割不存在已知蛋白酶的新靶标的能力，蛋白酶的应用将大大扩展。近日，哈佛大学医学院的研究团队开发了一种针对蛋白酶的噬菌体辅助进化系统，首次实现了对肉毒杆菌神经毒素 (Botulinum neurotoxin，BoNT)底物特异性的改变，创造出的新肉毒素突变体可在神经细胞里特异性切割对神经再生起阻碍作用的重要药物靶点蛋白PTEN（Phosphatase and tensin homolog）。而且，它们不再有效切割神经元中肉毒素BoNT蛋白酶的原本天然底物。该研究首次建立了一套完整的蛋白酶定向进化方法，并为重编程蛋白酶建立了一个通用平台，可用于选择性地切割具有治疗意义的新靶标。该研究团队运用 PACE 正负选择系统，重新编程了BoNT LC 蛋白酶的底物特异性。他们发明的PACE系统的主体是一个生物反应器，其中有M13噬菌体和大肠杆菌作为噬菌体的宿主。M13噬菌体基因组中的gIII基因被需要进化的蛋白酶基因所取代；而gIII基因放入了辅助质粒（Assisitant plasmid, AP）中，辅助质粒编码一个活性被T7 溶菌酶抑制的T7 RNA聚合酶和一个T7 启动子控制的gIII，T7 RNA聚合酶和T7溶解酶之间由一段蛋白酶可以识别并切割的底物多肽连接；突变质粒（Mutated plasimid, MP）则用于提高进化速率。当M13噬菌体感染大肠杆菌后，释放所编码的蛋白酶，切割了T3 RNA聚合酶和溶解酶之间的连接时，T3 RNA 聚合酶的活性得以释放，从而开始转录gIII，得到有侵染活性的噬菌体。反之则无法得到具有侵染活性的噬菌体。突变质粒则表达一些提高DNA复制时突变几率的蛋白，在噬菌体DNA复制时引入突变到蛋白酶的基因中，这样就完成了常规的提高蛋白酶活的正向筛选。在这项研究中，最具创意的部分就是，为了可以降低进化的蛋白酶对原始识别序列的活性，研究人员在原先正向选择的系统上，逆向的添加了一个反向选择系统。反向选择质粒编码一个由蛋白酶原始的识别序列多肽连接的T7‘ RNA 聚合酶和T7 溶菌酶，和一个由T7启动子控制的显性失活gIII。当噬菌体所编码的蛋白酶既可以激活正向选择质粒gIII的表达和反向选择质粒的显性失活gIII表达时，产生的新的噬菌体不具备感染性。也就是说，只有进化活性而没有原始活性的蛋白酶将会拥有选择优势而被筛选出来。当正向选择和反向选择同时进行时，就可以同步完成活性和选择性的进化。首先，为了验证系统的有效性，他们选择野生型的肉毒素X的轻链作为目标，利用PANCE系统将肉毒素X的偏好性向VAMP4和Ykt6进化。经过进化得到的突变体X(4130)B1和X(5010)B1分别对Ykt6和VAMP4的偏好性相对于VAMP1有了大幅提升。这两个肉毒素X轻链突变体也可以在全毒素的形式下被递送到体外培养的大鼠的神经元里切割其底物。进一步的，他们利用PACE的正向筛选逐渐将肉毒素F轻链进化为对VAMP7具有切割活性，这是一种已知肉毒素都不能切割的蛋白，但是它在蛋白的转运，分泌和细胞自噬中发挥重要作用。得到的突变体F(3041)B6虽然可以切割VAMP7，但是它还对保留有VAMP2的切割活性。又经过一系列的反向筛选，作者得到了另一个突变体F(3230)A3。这个突变体在体外酶活实验中展示了很高的VAMP7和极低的VAMP2切割活性，并在体内进行了验证。从晶体结构上来看，BoNT/X(4130)B1 的折叠与野生型 BoNT/X LC（PDB 6G47，rmsd=0.42 Å）相比基本没有变化。E166 突变将带负电荷的 Glu 侧链放置在从催化锌辅因子裂开的活性位点上。与 VAMP2 底物模拟物结合的相关 BoNT/F 蛋白酶的结构表明 E166 可能与底物的 P3 残基相互作用。推测 A166E 突变静电排斥 VAMP1 中的阴离子 P3 残基 (D66)，同时耐受 Ykt6 中的中性 P3 氨基酸 (V171)，从而有助于 Ykt6 选择性。第三步，他们完成了从无到有的工作，创造了一个切割新蛋白的酶。先前的VAMP7毕竟与其他VAMP蛋白具有较高的同源性，同属于SNARE蛋白。而将肉毒素E轻链从切割SNAP-25进化为特异性地切割磷酸酯酶PTEN则完全创造了一个新的蛋白酶。PTEN是一个磷酸酶，将PI3P转化为PI2P，负性调控细胞膜上的PI3P水平，从而抑制PI3K/AKT/mTOR信号通路并抑制细胞增殖。突变导致PTEN功能缺陷是一些细胞癌变的重要原因，因此PTEN也被认为是一种抑癌蛋白。但是在神经元再生方面，PTEN却起到了抑制再生的作用。在受损的中枢神经元中敲除PTEN已经被证明可以极大地提高神经元的再生能力。研究人员通过生物信息学比对选择了PTEN表面一段没有固定构像的肽段作为潜在的酶切靶点。这一段序列的20个氨基酸中仅有4个与SNAP-25 序列相同。经过一系列的双向筛选最终得到了突变体E(4130)A2。在体外酶活实验中，E(4130)A2对PTEN有较高的切割活性，而对SNAP-25的活性极低。但是当将E(4130)A2和PTEN共同表达在HEK293T细胞中时，并没有观察到明显的PTEN切割。他们分析也许由于PTEN在细胞膜上行使功能，而E(4130)A2主要在细胞质中，所以切割效率不如预期。当作者将定位在细胞膜上的PH结构域和E(4130)A2融合表达时，全长PTEN的水平显著下降。他们还通过病毒转染的方式在体外培养的大鼠皮质神经元中表达了PH-E(4130)A2，发现相对于对照组神经元中的PTEN水平有明显的下降，并且在神经细胞内部只有极低的SNAP-25切割活性。在E(4130)A2的基础上，作者根据肉毒素E识别SNAP-25蛋白结构方面的知识又加入了一个突变L167A，完全消除了对SNAP-25的切割活性。综上，本研究搭建的双向系统创造了从无到有的新蛋白酶，对进化不同蛋白都有良好的普适性。研究人员利用其完成了对肉毒素的重编程以识别一个全新的底物，创造了具有PTEN切割活性的锌蛋白酶PH-E(4130)A2以用于神经损伤后的再生。该技术也可以广泛应用于未来的蛋白酶和蛋白药物工程改造。参考文献Travis RB, Hao Liu, Michael SP, Xiaozhe Xiong, Pyung-Gang Lee, Sicai Zhang, Michelle Richter, George Minasov, Karla J F Satchell, Min Dong, David R Liu. Phage-assisted evolution of botulinum neurotoxin proteases with reprogrammed specificity. Science 2021, 371(6531):803-810.识别微信二维码，添加生物制品圈小编，符合条件者即可加入微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。