更新于：2024-04-01

CNTFR

睫状神经营养因子受体

更新于：2024-04-01

基本信息

别名

睫状神经营养因子受体、ciliary neurotrophic factor receptor、Ciliary neurotrophic factor receptor subunit alpha

+ [3]

简介

Binds to CNTF. The alpha subunit provides the receptor specificity. Receptor for heterodimeric neurotropic cytokine composed of CLCF1/CLC and CRLF1/CLF-1 (PubMed:26858303). Acts as a receptor for the neuroprotective peptide humanin as part of a complex with IL6ST/GP130 and IL27RA/WSX1 (PubMed:19386761).

关联

靶点

CNTFR

作用机制

CNTFR激动剂

在研机构

Brainstorm Cell Therapeutics, Inc.

原研机构

Tel-Aviv University

在研适应症

肌萎缩侧索硬化 [+7]

非在研适应症

阿尔茨海默症 [+3]

最高研发阶段申请上市

首次获批国家/地区-

首次获批日期1800-01-20

Ciliary neurotrophic factor(F. Hoffmann-La Roche Ltd.)

靶点

CNTFR

作用机制

CNTFR激动剂

在研机构-

原研机构

F. Hoffmann-La Roche Ltd.

在研适应症-

非在研适应症

肌萎缩侧索硬化

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

Recombinant Human Ciliary Neurotrophic Factor (Southwest China Biotech Base Co Ltd)

重组人睫神经营养因子

靶点

CNTFR

作用机制

CNTFR激动剂

在研机构-

原研机构

西南生物工程产业化中试基地有限公司

在研适应症-

非在研适应症

肥胖 [+1]

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 CNTFR 相关的临床试验

NCT04729972 / Completed临床2期

Phase II, Multicenter, Open-label Safety Study of Bilateral NT-501 in Participants With Macular Telangiectasia Type 2

This is a multi-center, open-label, 6-month study to evaluate the safety of bilateral CNTF implants in participants with Macular Telangiectasia Type 2.

开始日期2021-08-13

申办/合作机构

Neurotech Pharmaceuticals, Inc.

[+1]

NCT04577300 / Recruiting临床2期IIT

A Randomized, Sham Controlled, Masked Phase II Study to Evaluate the Safety and Efficacy of Dual Intravitreal Implantation of NT-501 Encapsulated Cell Therapy for the Treatment of Glaucoma

To determine the safety and efficacy over 24 months of dual NT-501 CNTF encapsulated cell therapy (ECT) on visual impairment related to glaucoma.

开始日期2021-05-15

申办/合作机构

Stanford University

NCT03799718 / Completed临床2期

A Phase 2 Open-label Multicenter Study to Evaluate the Safety and Efficacy of Repeated Administration of NurOwn® [Autologous Mesenchymal Stem Cells Secreting Neurotrophic Factors (NTF), MSC-NTF] Cells in Participants With Progressive MS

A multidose open-label study with autologous Mesenchymal Stromal Stem Cells Secreting Neurotrophic Factors (MSC-NTF cells) involving 20 participants with progressive MS at multiple investigational study sites.

开始日期2019-03-13

申办/合作机构

Brainstorm Cell Therapeutics, Inc.

100 项与 CNTFR 相关的临床结果

登录后查看更多信息

100 项与 CNTFR 相关的转化医学

登录后查看更多信息

0 项与 CNTFR 相关的专利（医药）

登录后查看更多信息

290

项与 CNTFR 相关的文献（医药）

2024-01-30·bioRxiv : the preprint server for biology

miR-26 deficiency causes alterations in lens transcriptome and results in adult-onset cataract.

作者: Anil Upreti ; Thanh V Hoang ; Minghua Li ; Jared A Tangeman ; David S Dierker ; Brad D Wagner ; Panagiotis A Tsonis ; Chun Liang ; Salil A Lachke ; Michael L Robinson

Purpose:

Despite strong evidence demonstrating that normal lens development requires regulation governed by miRNAs, the functional role of specific miRNAs in mammalian lens development remains largely unexplored.

Methods:

A comprehensive analysis of miRNA transcripts in the newborn mouse lens, exploring both differential expression between lens epithelial cells and lens fiber cells and overall miRNA abundance was conducted by miRNA-seq. Mouse lenses lacking each of three abundantly expressed lens miRNAs: miR-184, miR-26 and miR-1 were analyzed to explore the role of these miRNAs in lens development.

Results:

Mice lacking all three copies of miR-26 ( miR-26 ^TKO ) developed postnatal cataracts as early as 4-6 weeks of age. RNA-seq analysis of neonatal lenses from miR-26 ^TKO mice exhibited abnormal reduced expression of a cohort of genes found to be lens-enriched and linked to cataract ( e.g. Foxe3 , Hsf4 , Mip , Tdrd7, and numerous crystallin genes), and abnormal elevated expression of genes related to neural development ( Lhx3, Neurod4, Shisa7, Elavl3 ), inflammation ( Ccr1, Tnfrsf12a, Csf2ra) , the complement pathway, and epithelial to mesenchymal transition ( Tnfrsf1a, Ccl7, Stat3, Cntfr ).

Conclusion:

miR-1, miR-184 and miR-26 are each dispensable for normal embryonic lens development. However, loss of miR-26 causes lens transcriptome changes and drives cataract formation.

2023-10-01·International journal of radiation oncology, biology, physics

Intercellular Mechanisms of Therapeutic Resistance at the Tumor-Stromal Interface Using Ultra High-Plex Single-Cell Spatial Transcriptomics and Genetically-Engineered Tumoroids.

Article

作者: C Shiau ; J Cao ; M Gregory ; Y Kim ; S He ; J Reeves ; S Wang ; N A Lester ; J Su ; P L Wang ; J Beechem ; T S Hong ; J Y Wo ; D Ting ; M Hemberg ; W L Hwang

PURPOSE/OBJECTIVE(S):

There is a major gap in knowledge regarding how intercellular interactions in the tumor microenvironment (TME) mediate therapeutic resistance. Achievement of this goal has been limited by a lack of (1) spatial context in dissociated single-cell methods; (2) single-cell resolution in spatial profiling approaches; (3) high quality data and yield with FFPE patient specimens; and (4) computational methods for ligand-receptor analyses that consider both gene expression and spatial coordinates.

MATERIALS/METHODS:

We developed an innovative spatial biology paradigm that combines cutting-edge experimental and computational methods to enable high-resolution, spatially-guided discovery of critical mediators of therapeutic resistance. We applied this approach to dissect the single-cell spatial transcriptomic landscape of untreated vs. chemoradiotherapy-treated primary human pancreatic ductal adenocarcinoma (PDAC; n = 21) using ultra-high plex spatial molecular imaging (SMI) optimized for high-sensitivity, subcellular detection of up to 6000 gene transcripts in FFPE sections-an order of magnitude greater than contemporary methods.

RESULTS:

We recovered over 1,000,000 high-quality single cells in situ representing more than 20 distinct cell types, including epithelial, immune, endothelial, endocrine, and diverse stromal cells. We developed an optimal transport-based computational method to infer cell-cell communication at the cancer-stromal interface. Treatment with chemoradiotherapy was associated with the largest increase in fibroblast-malignant interactions. Comparing the SMI data with orthogonal single-nucleus RNA-sequencing and digital spatial profiling data, we identified CLCF1-CNTFR as the fibroblast-malignant interaction most associated with resistance to chemoradiotherapy in PDAC. CLCF1 is a gp130-family cytokine that activates Jak-STAT signaling and acts as a potent neurotrophic factor. Notably, the CLCF1-CNTRF (fibroblast-malignant) interaction has prominent pro-oncogenic effects in lung adenocarcinoma and an engineered CNTFR decoy receptor with therapeutic potential has been developed. To functionally validate the role of the CLCF1-CNTFR (fibroblast-malignant) interaction in mediating resistance to cytotoxic therapy, we created CRISPR-engineered cancer-fibroblast tumoroids and modulated expression of this ligand-receptor pair. Pancreatic cancer cell viability in the presence of 5-fluorouracil was better maintained with increased CLCF1-CNTFR signaling.

CONCLUSION:

In this study, we integrated ultra high-plex single-cell spatial transcriptomics, optimal transport ligand-receptor predictions, and genetically-engineered stromal tumoroids to identify and validate CLCF1-CNTFR as an important intercellular mechanism of resistance to chemoradiotherapy in PDAC-pioneering a paradigm for translating single-cell spatial biology to clinical oncology.

2023-08-16·BMC genomics

Transcriptome analysis of multiple tissues reveals the potential mechanism of death under acute heat stress in chicken.

Article

作者: Jiuhong Nan ; Hongrui Yang ; Li Rong ; Zijia Jia ; Sendong Yang ; Shijun Li

BACKGROUND:

Acute heat stress could induce high mortality and cause huge economic losses in the poultry industry. Although many studies have revealed heat stress-induced injuries of multiple tissues, the main target tissue and molecular mechanism of death under acute heat stress was largely unknown. This study systematically compared the transcriptome data of five main visceral tissues in chickens to reveal the response of multiple tissues to acute heat stress and determine the main target tissue of acute heat stress, further revealing the injuries of main target tissue and their potential mechanism by combing pathological section and qRT-PCR technologies.

RESULTS:

The transcriptome data of five visceral tissues revealed that acute heat stress broadly caused inflammatory response and damaged tissues metabolic homeostasis. Among the five tested visceral tissues, the number of differentially expressed genes in the lung was the highest, and their fold changes were the greatest, indicating that the lung was the main target tissue of acute heat stress. The results of pathological section revealed severe inflammation, emphysema and pulmonary hemorrhage in the lung under acute heat stress. Our study found that some pro-inflammatory genes, including CNTFR, FURIN, CCR6, LIFR and IL20RA, were significantly up-regulated both in the heat-stress and heat-death groups, and their fold changes in the heat-death group were significantly greater than that in the heat-stress group. We also found an anti-inflammatory gene, AvBD9, exhibiting an extremely high expression in the heat-stress group but a low expression in the heat-death group.

CONCLUSIONS:

Our study found that acute heat stress caused multiple tissue injuries broadly and the lung was the main target tissue of acute heat stress in chicken. Acute heat stress caused a severe inflammatory response, emphysema, and pulmonary haemorrhage, The severe inflammatory response in the heat-death group was related to the up-regulation of pro-inflammatory genes and down-regulation of anti-inflammatory genes.

项与 CNTFR 相关的新闻（医药）

2024-03-22

·生物制品圈

一文读懂 | IL-12 mRNA蛋白替代疗法实体瘤研究进展

导读：L-12是一种天然存在的细胞因子，在机体对癌症的免疫抑制过程中起着关键作用，作为免疫治疗药物有着悠久的历史。尽管在多项临床前研究中IL-12始终显示出有效的抗肿瘤活性，但在人体可耐受剂量下，重组IL-12蛋白在临床试验中无法显示其应有的治疗效果。IL-12作用于其受体 (IL-12Rβ1/IL-12Rβ2) 会触发高水平的 IFNγ，IFNγ 是其主要下游介质，不仅影响疗效，而且影响全身毒性。由于严重的安全问题，静脉注射重组蛋白试验被停止。如果全身给药，则很难保证机体安全。因此，人们开始利用各种递送系统探索 IL-12肿瘤局部和瞬时基因表达，从而避免药物毒性。采用脂质纳米颗粒（LNP）局部递送IL-12-mRNA 是一种技术替代。本期文章菌菌解析了IL-12特征、信号通路以剖析IL-12 mRNA的成药潜力，菌菌同时汇总了IL-12 mRNA的管线研究现状。采用病毒载体和肺病毒载体瘤内递送IL-12实现抗肿瘤功效01IL-12靶点成药潜力1.1 IL-12蛋白结构IL-12是一种由IL-12A编码的 35kDa亚基（p35）和IL-12B编码的40 kDa 亚基(p45)组成的异二聚体糖蛋白，是唯一已知由二硫键连接的异二聚体细胞因子，也称为 p70。p35亚基的一级序列与其他1类细胞因子显示出同源性，特别是 IL-6 和粒细胞集落刺激因子 (G-CSF)，该家族成员的蛋白结构特点是四螺旋束拓扑。p40 亚基与已知的细胞因子不同源，但在一级序列上与造血细胞因子受体家族成员 IL-6 受体α链 (IL-6Rα) 和睫状神经营养因子受体 (CNTFR) 的胞外结构域相似。与 IL-6Rα和CNTFR 一样，p40 包含一个N末端免疫球蛋白 (Ig) 结构域，后跟两个 III 型纤连蛋白结构域。第一个纤连蛋白结构域包含四个保守的半胱氨酸，而第二个包含所有家族成员共有的WSXWS 框。Human IL-12A SequenceHuman IL-12B Sequence类似于可溶性 1 类细胞因子α受体的p40亚基。N-和C-末端分别标记为蛋白序列的N和C。三个结构域分别标记为D1、D2和D3。黄色表示链内二硫键，红色表示N-连接糖修饰和，洋红色表示WSXWS 基序。松绿石色表示与p35接触的环位于 D2 和 D3 之间的顶点。类似于可溶性 1 类细胞因子-受体复合物的p70。p35（粉红色）具有标记为 A-D 的典型四螺旋束，p40（蓝色）具有标记为 D1-D3 的结构域，链间二硫键（黄色，箭头），分子内二硫键（黄色），N 连接糖基化（红色）以及标记 N 和 C 的 N 和 C 末端。结构表位也被突出显示：来自 p40 环 1、3、5 和 6（绿松石）的残基与来自 AD 螺旋面（薰衣草）和二硫键环（洋红色）的 p35 残基接触。p35 R189侧链（绿色）从螺旋D延伸，埋在p40环内。许多细胞因子受体（包括 IL-6Rα）可以通过蛋白水解或选择性剪接产生，以可溶形式（缺乏跨膜和短胞质结构域）从细胞中释放。可溶性 IL-6Rα 可以在溶液中结合 IL-6，并且该复合物通过与表达 gp130（IL-6R 信号复合物的 β 链）的细胞结合来介导 IL-6 信号传导。因此，IL-12 可以被认为是与细胞因子p35共价结合的可溶性细胞因子受体α链 (p40)，其细胞表面受体与 gp130 具有类似的功能。尽管 p35 转录物存在于许多细胞类型中，但游离的 p35 并不分泌，这表明 p35 在缺乏 p40 的情况下不稳定。有趣的是，游离的 p40 被分泌出来，无论是作为单体还是作为二硫键连接的同二聚体，均在小鼠中可作为 IL-12 信号传导的拮抗剂。1.2 IL-12信号通路及功能IL-12由抗原呈递细胞产生，包括树突状细胞、巨噬细胞/单核细胞、中性粒细胞和一些B细胞。IL-12作为一种强效的免疫调节细胞因子，对于针对胞内病原体的细胞免疫至关重要。IL-12具有多种生物活性，包括增强NK细胞和细胞毒性T细胞的活性、刺激活化的NK细胞或者T细胞增殖及诱导释放IFN-γ。IL-12 还通过诱导 1 类 T 辅助细胞 (Th1) 免疫反应来促进细胞介导的免疫，从而在免疫调节中发挥重要作用。p35-p40异二聚体通过与 gp130 高度同源的跨膜受体（由两个亚基IL-12Rβ1 和IL-12Rβ2组成）相互作用来启动信号通路。该受体的每个亚基由一个胞外配体结合结构域、一个跨膜结构域和一个含有介导Janus家族酪氨酸激酶结合的框1和框2序列的胞质结构域组成。 IL-12结合被认为会导致β1和β2异二聚化，并产生能够进行信号转导的高亲和力受体复合物。在该模型中，受体的二聚化导致胞质结构域并置，随后酪氨酸磷酸化并激活受体相关的 Janus 家族激酶 Jak2 和 Tyk-2。这些激活的激酶反过来使酪氨酸磷酸化并激活信号转导子和转录激活子 (STAT) 家族的几个成员（STAT-1、-3 和 -4）。STAT 易位至细胞核以激活多个基因的转录，包括 IFN-γ。IFN-γ的产生在细胞中具有多效性，刺激对细胞介导的免疫重要的分子的产生。特别是，IFN-γ刺激更多IL-12的产生，并在IL-12信号传导和IFN-γ之间建立正向调节环。IL-12和STAT-4敲除小鼠的IFN-γ产生严重受损，证明了IL-12对于该环的重要性。IL-12-IFN-γ 细胞因子通路02IL-12mRNA研究现状Moderna与AstraZenecaModerna作为将mRNA技术应用到肿瘤治疗的先驱者，与AstraZeneca共同合作，致力于采用mRNA-LNP递送系统瘤内递送IL-12，发挥其应有的抗肿瘤活性，研发出MEDI1191药物，并且在临床1期试验中证实了MEDI1191的安全性和抗肿瘤活性。后续文章中，菌菌将深度解析Moderna瘤内注射药物IL-12 mRNA-LNP（MEDI1191）序列设计、机制研究和临床研究结果。嘉晨西海2022年3月30日，嘉晨西海宣布其自主研发的JCXH-211获得FDA临床批件，CXH-211是一种基于自复制 mRNA的编码人白细胞介素-12（hIL-12）的新型药物，用于晚期实体肿瘤治疗，是全球首款表达细胞因子的自复制mRNA药物。据公开信息显示，评估JCXH-211安全性的I期临床试验（NCT05727839）正在开展。据嘉晨西海报道，JCXH-211在临床前研究的多个小鼠和 PDX 疾病模型中都表现出了优异的肿瘤清除效力，优于采用传统非复制mRNA的类似研究药物。数据显示，JCXH-211在小鼠模型中能有效杀伤肿瘤细胞，消除远端瘤，并预防肿瘤复发。这一优异的肿瘤清除效果来源于RNA 复制子（RNA replicon）引发的强烈的抗病毒免疫反应以及 IL-12 激活的强效抗肿瘤免疫反应。同时，JCXH-211在综合 GLP 毒理学研究中显示出了近乎完美的安全性。除常规mRNA和自复制RNA(saRNA)外，近年来环状RNA(circRNA)也备受关注。耀海生物基于三种RNA技术，设计并制备了IL-12 mRNA、IL-12 saRNA和IL-12 circRNA预制品，均在细胞中高表达。艾博生物2023年6月，艾博生物编码人源细胞因子IL-12的mRNA脂质纳米球注射液（ABO2011）获得国内临床批件，此为艾博首个获批IND的肿瘤领域mRNA产品，给药方式同样为瘤内注射。ABO2011当前正在开展I期临床试验（CTR20232745），拟纳入人群为二线及以上的晚期实体瘤患者。03总结IL-12是一种前景广阔的抗肿瘤药物。它参与了naive T细胞向Th1细胞的分化，被认为是T细胞刺激因子，可诱导T细胞增殖。同时，它可以增强对细胞毒性淋巴细胞和自然杀伤细胞（NK）的激活以及增加干扰素（IFNγ）的产生。由于其促炎和免疫调节的能力，它可以使肿瘤由“冷”变成“热”。目前，国内外的mRNA研发公司将IL-12列为重点管线，积极布局。Moderna已公布其与阿斯利康合作管线IL-12 mRNA-LNP（MEDI1191）的首次临床结果，下篇文章菌菌将解析MEDI1191的序列设计，并持续更新其机制研究和临床研究结果，敬请关注！参考文献 [1] Hewitt SL, Bailey D, Zielinski J, et al. Intratumoral IL12 mRNA Therapy Promotes TH1 Transformation of the Tumor Microenvironment. Clin Cancer Res. 2020 Dec 1;26(23):6284-6298. doi: 10.1158/1078-0432.CCR-20-047.[2] Cirella A, Berraondo P, Di Trani CA, Melero I. Interleukin-12 Message in a Bottle. Clin Cancer Res. 2020 Dec 1;26(23):6080-6082. doi: 10.1158/1078-0432.CCR-20-3250.[3] O. Hamid, M. Hellman, B. Carneiro, et al. Preliminary safety, antitumor activity and pharmacodynamics results of HIT-IT MEDI1191 (mRNA IL-12) in patients with advanced solid tumours and superficial lesions. ABSTRACT. doi:10.1016/j.annonc.2021.01.033. 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生物制品微信群！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。

信使RNA临床结果免疫疗法临床1期