更新于：2024-11-01

regnase-1

更新于：2024-11-01

基本信息

别名

Endoribonuclease ZC3H12A、FLJ23231、MCP-induced protein 1

+ [9]

简介

Endoribonuclease involved in various biological functions such as cellular inflammatory response and immune homeostasis, glial differentiation of neuroprogenitor cells, cell death of cardiomyocytes, adipogenesis and angiogenesis. Functions as an endoribonuclease involved in mRNA decay (PubMed:19909337). Modulates the inflammatory response by promoting the degradation of a set of translationally active cytokine-induced inflammation-related mRNAs, such as IL6 and IL12B, during the early phase of inflammation (PubMed:26320658). Prevents aberrant T-cell-mediated immune reaction by degradation of multiple mRNAs controlling T-cell activation, such as those encoding cytokines (IL6 and IL2), cell surface receptors (ICOS, TNFRSF4 and TNFR2) and transcription factor (REL) (By similarity). Inhibits cooperatively with ZC3H12A the differentiation of helper T cells Th17 in lungs. They repress target mRNA encoding the Th17 cell-promoting factors IL6, ICOS, REL, IRF4, NFKBID and NFKBIZ. The cooperation requires RNA-binding by RC3H1 and the nuclease activity of ZC3H12A (By similarity). Together with RC3H1, destabilizes TNFRSF4/OX40 mRNA by binding to the conserved stem loop structure in its 3'UTR (By similarity). Self regulates by destabilizing its own mRNA (By similarity). Cleaves mRNA harboring a stem-loop (SL), often located in their 3'-UTRs, during the early phase of inflammation in a helicase UPF1-dependent manner (PubMed:19909337, PubMed:26320658, PubMed:26134560, PubMed:22561375). Plays a role in the inhibition of microRNAs (miRNAs) biogenesis (PubMed:22055188). Cleaves the terminal loop of a set of precursor miRNAs (pre-miRNAs) important for the regulation of the inflammatory response leading to their degradation, and thus preventing the biosynthesis of mature miRNAs (PubMed:22055188). Also plays a role in promoting angiogenesis in response to inflammatory cytokines by inhibiting the production of antiangiogenic microRNAs via its anti-dicer RNase activity (PubMed:24048733). Affects the overall ubiquitination of cellular proteins (By similarity). Positively regulates deubiquitinase activity promoting the cleavage at 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains on TNF receptor-associated factors (TRAFs), preventing JNK and NF-kappa-B signaling pathway activation, and hence negatively regulating macrophage-mediated inflammatory response and immune homeostasis (By similarity). Induces also deubiquitination of the transcription factor HIF1A, probably leading to its stabilization and nuclear import, thereby positively regulating the expression of proangiogenic HIF1A-targeted genes (PubMed:24048733). Involved in a TANK-dependent negative feedback response to attenuate NF-kappaB activation through the deubiquitination of IKBKG or TRAF6 in response to interleukin-1-beta (IL1B) stimulation or upon DNA damage (PubMed:25861989). Prevents stress granule (SGs) formation and promotes macrophage apoptosis under stress conditions, including arsenite-induced oxidative stress, heat shock and energy deprivation (By similarity). Plays a role in the regulation of macrophage polarization; promotes IL4-induced polarization of macrophages M1 into anti-inflammatory M2 state (By similarity). May also act as a transcription factor that regulates the expression of multiple genes involved in inflammatory response, angiogenesis, adipogenesis and apoptosis (PubMed:16574901, PubMed:18364357). Functions as a positive regulator of glial differentiation of neuroprogenitor cells through an amyloid precursor protein (APP)-dependent signaling pathway (PubMed:19185603). Attenuates septic myocardial contractile dysfunction in response to lipopolysaccharide (LPS) by reducing I-kappa-B-kinase (IKK)-mediated NF-kappa-B activation, and hence myocardial pro-inflammatory cytokine production (By similarity). (Microbial infection) Binds to Japanese encephalitis virus (JEV) and Dengue virus (DEN) RNAs. (Microbial infection) Exhibits antiviral activity against HIV-1 in lymphocytes by decreasing the abundance of HIV-1 viral RNA species.

关联

项与 regnase-1 相关的药物

KSQ-004

靶点

SOCS1 x regnase-1

作用机制

SOCS1调节剂 [+1]

在研机构

KSQ Therapeutics, Inc.初创企业

原研机构

KSQ Therapeutics, Inc.初创企业

在研适应症

晚期恶性实体瘤

非在研适应症-

最高研发阶段临床1/2期

首次获批国家/地区-

首次获批日期1800-01-20

Anti-SOCS1/Regnase-1 CAR-T(KSQ)

SOCS1/Regnase-1靶向CAR-T(KSQ)

靶点

SOCS1 x regnase-1

作用机制

SOCS1调节剂 [+1]

在研机构

KSQ Therapeutics, Inc.初创企业

原研机构

KSQ Therapeutics, Inc.初创企业

在研适应症

实体瘤

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

Regnase-1(Ribometrix)

靶点

regnase-1

作用机制

regnase-1抑制剂

在研机构

Ribometrix, Inc.初创企业

原研机构

Ribometrix, Inc.初创企业

在研适应症

肿瘤

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

项与 regnase-1 相关的临床试验

NCT06598371 / Not yet recruiting临床1/2期IIT

A Phase 1/2 Study of KSQ-004EX, Autologous Tumor Infiltrating Lymphocytes Engineered to Inactivate Genes Encoding SOCS1 and Regnase-1, in Patients With Select Advanced Solid Tumors

Phase 1 is to find the recommended dose of KSQ-004EX to give to participants with advanced solid tumors.
Phase 2 is to learn if KSQ-004EX at the recommended dose found in Phase1 can help to control advanced solid tumors.
The safety and effects of KSQ-004EX will also be studied in both phases.

开始日期2025-03-11

申办/合作机构

The University of Texas MD Anderson Cancer Center

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100 项与 regnase-1 相关的临床结果

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100 项与 regnase-1 相关的转化医学

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0 项与 regnase-1 相关的专利（医药）

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608

项与 regnase-1 相关的文献（医药）

2024-10-01·Biochimica et Biophysica Acta (BBA) - General Subjects

Keratinocyte and myeloid MCPIP1 have distinct roles in maintaining skin homeostasis

Article

作者: Rumienczyk, Izabela ; Mikula, Michal ; Szukala, Weronika ; Zawada, Roza ; Goryca, Krzysztof ; Lichawska-Cieslar, Agata ; Jura, Jolanta

The skin is a complex organ, and the intricate network between keratinocytes and immune cells is critical for ensuring skin function. Monocyte chemotactic protein-1-induced protein 1 (MCPIP1) is a ribonuclease that functions as a key negative modulator of inflammation. We previously reported that conditional deletion of MCPIP1 in keratinocytes (Mcpip1^EKO) impairs skin integrity in adult mice. A similar phenotype was observed following the depletion of MCPIP1 in the myeloid compartment (Mcpip1^MKO). The aim of this study was to develop a keratinocyte and myeloid double-MCPIP1 knockout mouse model to clarify the specific roles of myeloid and epidermal MCPIP1 in skin biology. Histological analyses indicated that the skin morphology changed after depletion of MCPIP1 in cells of myeloid origin as well as in keratinocytes. The thicknesses of the epidermal and subcutaneous fat layers increased in the mice with a loss of epidermal MCPIP1, whereas the loss of myeloid MCPIP1 had the opposite effect. In addition, both types of mice showed opposite responses to stimulation with 12-O-tetradecanoylphorbol-13-acetate. Transcriptomic profiling of whole-skin lysates revealed some common target transcripts in all the knockout mice. Further analyses revealed that distinct pathways are modulated following the loss of epidermal or myeloid MCPIP1. The skin morphology and inflammatory phenotype of keratinocyte and myeloid double-MCPIP1 knockout mice resembled those of mice with only keratinocyte-specific knockout of MCPIP1. Overall, myeloid and epidermal MCPIP1 play important but distinct roles in the modulation of skin-related processes.

2024-09-30·The FASEB Journal

MCPIP1 promotes atrial remodeling by exacerbating miR‐26a‐5p/FRAT/Wnt axis–mediated atrial fibrosis in a rat model susceptible to atrial fibrillation

Article

作者: Tang, Baopeng ; Huang, Wenchao ; Zhang, Wanfeng ; Zhou, Xianhui ; Li, Kai ; Bo, Yakun ; Sun, Huaxin ; Lu, Yanmei ; Guo, Yankai ; Yang, Hang ; Zhao, Yang ; Zhang, Ling

AbstractAtrial fibrosis plays a critical role in the pathogenesis of atrial fibrillation (AF). Monocyte chemotactic protein–induced protein‐1 (MCPIP1), recognized as a functional ribonuclease (RNase), exacerbates cardiac remodeling and contributes to a range of cardiovascular diseases. However, the involvement of MCPIP1 in atrial fibrosis and development of AF, along with its underlying biological mechanisms, remains poorly understood. This study demonstrated that knockdown of MCPIP1 significantly reduced AF inducibility, decreased left atrial diameter, and ameliorated atrial fibrosis, coinciding with reduced FRAT1/2/Wnt/β‐catenin signaling. Furthermore, the MCPIP1‐D141N mutation attenuated AF vulnerability and atrial remodeling compared to MCPIP1 overexpression in an acetylcholine and calcium chloride (ACh‐CaCl2)–induced rat model of AF. Conversely, overexpression of FRAT1/2 partially reversed the cardioprotective effects of MCPIP1‐D141N mutation. Using H9C2 cell lines, we observed that MCPIP1 may induce a transcriptional effect that downregulates miR‐26a‐5p expression, and luciferase and RNA immunoprecipitation (RIP) assays substantiated the direct interaction between miR‐26a‐5p and FRAT1/2. Moreover, overexpression of miR‐26a‐5p countered MCPIP1‐induced atrial remodeling and attenuated the progression of AF. In conclusion, these findings indicate that MCPIP1 facilitates atrial remodeling and the progression of AF by exacerbating miR‐26a‐5p/FRAT/Wnt axis–mediated atrial fibrosis through its RNase activity in an ACh‐CaCl2–induced rat model of AF.

2024-09-19·Oncogene

SUV39H1 epigenetically modulates the MCPIP1-AURKA signaling axis to enhance neuroblastoma tumorigenesis.

Article

作者: Sun, Feifei ; Song, Mengjia ; Zhang, Yizhuo ; Lu, Suying ; Zhang, Yu ; Xie, Weiji ; Li, Mengzhen ; Xiong, Xiangyu ; Wang, Juan ; Zhu, Jia ; Que, Yi ; Huang, Junting ; Chen, Huimou

Epigenetic regulation is a pivotal factor during neuroblastoma (NB) pathogenesis and investigations into cancer epigenetics are actively underway to identify novel therapeutic strategies for NB patients. SUV39H1, a member of the H3K9 methyltransferase family, contributing to tumorigenesis across multiple malignancies. However, its specific role in NB remains unexplored. In this study, we conducted a high-throughput screen utilizing a compound library containing 288 epigenetic drugs, leading to the identification of chaetocin as the most potent NB inhibitor by targeting SUV39H1. Genetic manipulation and therapeutic inhibition of SUV39H1 significantly impacted proliferation, migration, cell cycle phases, and apoptosis in NB cells. Concurrently, chaetocin demonstrated robust anti-tumor efficacy in vivo with tolerable toxicity. RNA-seq unveiled that SUV39H1 knockdown and inhibition down-regulated cell cycle pathways, impacting vital genes such as AURKA. Besides, MCPIP1 emerged as a novel tumor suppressor following SUV39H1 inhibition, which decreased AURKA expression in NB. In detail, SUV39H1 mediated the enrichment of H3K9me3 at the promoter region of MCPIP1, repressing the MCPIP1-mediated degradation of AURKA and facilitating the subsequent accumulation of AURKA, which revealed the oncogenic role of SUV39H1 via the SUV39H1-MCPIP1-AURKA signaling axis in NB. Therapeutic inhibition of SUV39H1 using chaetocin emerges as an effective and safe strategy for NB patients. Illustration of the oncogenic pathway regulated by SUV39H1 in NB.

项与 regnase-1 相关的新闻（医药）

2024-09-28

·药明康德

功能性治愈糖尿病的干细胞疗法；首个工程化B细胞疗法公布积极临床进展…… | CGT周报

▎药明康德内容团队编辑近期，全球细胞和基因疗法（CGT）领域迎来系列进展。自体基因编辑造血干细胞疗法Casgevy在加拿大获批上市，用于治疗12岁及以上镰刀型细胞贫血病（SCD）伴复发性血管闭塞危象（VOCs）患者，以及输血依赖性β地中海贫血（TDT）患者。Capricor Therapeutics公司的杜氏肌营养不良（DMD）细胞疗法deramiocel即将递交上市申请。首个进入人体临床试验的工程化B细胞疗法ISP-001的1期临床试验数据积极。邓宏魁教授合作团队开发的利用化学重编程诱导多能干细胞制备的胰岛细胞在临床试验中使1名1型糖尿病患者实现了临床功能性治愈。本文将节选其中部分重要进展做简单介绍，仅供读者参阅。图片来源：123RF ———✦研发进展✦——— ◇ Vertex Pharmaceuticals公司宣布，加拿大卫生部已批准自体基因编辑造血干细胞疗法Casgevy（exagamglogene autotemcel，exa-cel）上市，用于治疗12岁及以上SCD伴复发性VOCs患者，以及TDT患者。这项批准是基于两项全球正在进行的临床试验（针对SCD患者的CLIMB-121研究和针对TDT患者的CLIMB-111研究）的积极中期结果。两项试验均达到了主要终点，即患者至少连续12个月没有发生重度VOC或不需进行输血。其安全性与使用白消安清髓性预处理和造血干细胞移植基本一致。 2023年11月，Casgevy获英国药品和健康产品管理局（MHRA）有条件上市许可，用于治疗12岁及以上SCD与TDT患者，成为全世界首款获批上市的CRISPR基因编辑疗法。美国FDA并于2023年12月与今年1月先后批准该疗法用于治疗SCD与TDT患者。今年2月，欧盟委员会（EC）授予该疗法有条件上市许可，用于治疗12岁及以上SCD与TDT患者。 ◇ Capricor Therapeutics公司宣布，在与美国FDA完成近期会议后，该公司计划基于现有的心脏数据和自然病史数据，为其在研细胞疗法deramiocel（CAP-1002）递交生物制品许可申请（BLA），用于治疗DMD相关心肌病患者。该BLA申请预计在2024年10月启动递交，并在2024年底完成全部提交。此前公布的HOPE-2开放标签扩展研究数据显示，接受deramiocel治疗的患者评估上肢功能的指标获得统计显著改善。 Deramiocel是一种来源于健康人类心脏的基质细胞。它们通过释放包含微RNA、非编码RNA和蛋白的外泌体，改善DMD患者肌肉瘢痕或纤维化以及心脏功能。Deramiocel还显示出有效的免疫调节活性，可能促进细胞再生。目前美国FDA已授予deramiocel再生医学先进疗法认定与孤儿药资格。 ◇ Immusoft公司公布了其工程化B细胞疗法ISP-001用于治疗1型黏多糖贮积症（MPS I）的1期临床试验中首例患者的积极结果。分析显示，该名成年患者展现药效学和身体功能上的改善，并且在生活质量和日常生活活动上获得了显著的进步。患者与MPS I相关的疼痛也获得减轻。安全性方面，ISP-001的耐受性良好。截至2024年9月19日，尚未报告任何不良事件。 MPS I是一种罕见且致命的儿童遗传病，会影响身体产生α-L-艾杜糖苷酸酶（IDUA，一种有助于分解细胞内长链糖的必需酶）的能力。糖链若无法分解会在细胞中积聚并造成渐进性损伤，这种积聚会发生在包括大脑的组织中。ISP-001细胞使用“睡美人”转座子系统（Sleeping Beauty transposon system）表达α-L-艾杜糖苷酶，从而改善MPS I症状。ISP-001已获得FDA的孤儿药资格和MPS I的罕见儿科疾病认定。根据新闻稿，ISP-001是首个进入人体临床试验的工程化B细胞疗法。 ◇ KSQ Therapeutics公司宣布美国FDA已经批准其工程化肿瘤浸润淋巴细胞（TIL）疗法KSQ-004EX的IND申请。KSQ-004EX由患者来源的TIL组成，这些细胞中编码SOCS1和Regnase-1的基因通过CRISPR/Cas9基因编辑被灭活，有望彻底改变实体瘤的治疗。在临床前研究中，KSQ-004EX在对PD-1抑制剂难治的实体瘤模型中显示出更强的抗肿瘤功能。 ◇ Minovia Therapeutics公司宣布，美国FDA已批准其自体造血干细胞产品MNV-201的IND申请，支持其启动MNV-201在低风险骨髓增生异常综合征（MDS）患者中的1b期剂量探索临床试验。MNV-201是一种富含异体线粒体的自体造血干细胞产品。该产品旨在恢复低风险MDS患者造血干细胞的线粒体功能，从而改善向红细胞谱系的分化，并有可能改善贫血。临床前研究表明，MNV-201有可能实现安全给药、低免疫原性风险和规模化生产，以满足大量可能符合MNV-201治疗条件的患者的需求。 ◇ 中国国家药监局药品审评中心（CDE）官网公示显示，合源生物纳基奥仑赛注射液新适应症上市申请获得受理。纳基奥仑赛为一款靶向CD19的自体嵌合抗原受体T（CAR-T）细胞注射液。根据合源生物官网研发管线推测，本次申报上市的适应症可能是复发/难治性B细胞非霍奇金淋巴瘤（r/r B-NHL）。针对该适应症，纳基奥仑赛注射液正处于关键性2/3期临床研究阶段。今年6月，合源生物在欧洲血液学协会年会（2024 EHA）以壁报形式公布了纳基奥仑赛注射液治疗复发或难治性大B细胞淋巴瘤的1期临床试验长期随访结果。截至2022年11月1日，中位随访时间24.1个月，客观缓解率（ORR）为66.7%，完全缓解率（CR）为55.6%，中位持续缓解时间（DOR）和总生存期（OS）尚未到达，2年的无进展生存率和总生存率分别为33.3%和66.7%。研究人员认为，纳基奥仑赛注射液在复发或难治性大B细胞淋巴瘤患者中显示出良好的安全性和疗效。 ◇ 近日，由天津市第一中心医院沈中阳教授、王树森研究员，与北京大学、昌平实验室邓宏魁教授合作领衔的研究团队开发的干细胞再生疗法治疗1型糖尿病的临床研究结果登上《细胞》杂志。在该临床研究中，患者接受了利用化学重编程诱导多能干细胞制备的胰岛细胞。目前，首例患者已恢复了内源自主性、生理性的血糖调控，移植75天后完全稳定地脱离胰岛素注射治疗，目前疗效已稳定持续1年以上，实现了临床功能性治愈。 ▲该名1型糖尿病患者的治疗效果（图片来源：参考资料[7]）邓宏魁教授表示，化学重编程技术制备的功能细胞在临床治疗疾病的成功，表明化学重编程有望成为高效制备各种功能细胞类型的通用底层技术，为细胞治疗在重大疾病治疗上的广泛应用开辟了新的道路。 ◇ 精准生物宣布，其注射用MC-1-50细胞制剂用于治疗成人难治性系统性红斑狼疮（SLE）的IND申请获国家药品监督管理局审评中心（CDE）正式受理。MC-1-50是该公司自主研发的、基于PRIMCAR平台开发的第二代靶向CD19的CAR-T细胞疗法，具备更低剂量、更小副作用、更持久的特点。此次获批的适应症是MC-1-50继B细胞急性淋巴细胞白血病和非霍奇金淋巴瘤后获受理的第三项适应症。 ———✦融资、合作、M&A✦——— 图片来源：123RF ◇ Genespire公司宣布完成4600万欧元（约5200万美元）的B轮融资，获得资金将支持该公司的核心候选产品GENE202的开发，直至进入治疗甲基丙二酸血症（MMA）的1/2期临床试验。本轮B轮融资还将加强公司产品管线，促进针对多种其他遗传疾病候选疗法的发现和临床前研究。 MMA是一种破坏某些氨基酸和脂肪代谢的严重遗传疾病，通常在婴儿早期发病，伴随高死亡率，临床表现包括肌无力、癫痫、发育迟缓和器官损伤。目前，尚无可改变MMA疾病进程的治疗方法。GENE202是一种现货型基因疗法，利用了该公司的免疫屏蔽慢病毒载体（ISLV）平台。GENE202设计为可静脉注射，使患者的肝脏终生产生该疗法。ISLV的作用机制使Genespire的治疗方法特别适用于当前面临最紧迫未满足医疗需求的遗传病儿童患者，同时也能惠及成人患者。 ◇ 星赛瑞真宣布完成数千万元天使轮融资，并正式启动了天使+轮融资计划。本轮融资由复星医药旗下复健资本新药创新基金和创瑞投资嘉兴创琰基金共同投资，所得资金将用于核心管线和平台的持续推进，以及公司团队及研发实验室建设。星赛瑞真致力于通过再生医学技术创新和卓越的诱导多能干细胞（iPSC）器官移植替代产品的研发，为等待器官移植的患者带来革命性的治疗选择。该公司建成了3个iPSC再生医学技术平台，包括CRG-iPSC（体细胞重编程平台）、CRG-EDIT（基因编辑平台）和CRG-XDIF（干细胞多向分化平台）。其研发管线目前有两款在研产品，iPSC衍生异体角膜内皮细胞产品CRG-101即将推进至临床申报阶段，iPSC衍生β-胰岛细胞产品CRG-002尚处于临床前研发阶段。 ◇ 近日，信念医药宣布与拜耳集团的全资独立运营的基因疗法子公司Asklepios BioPharmaceutical达成战略合作，将共同探索创新基因疗法潜力。根据合同条款，双方将结合各自在基因治疗技术方面的专业积淀和优势力量，深入研究和探索通过肝脏靶向治疗途径实现创新基因治疗方案的疾病领域。 ▲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（可上下滑动查看） [1] Health Canada Grants Marketing Authorization of First CRISPR/Cas9 Gene-Edited Therapy, CASGEVY® (Exagamglogene Autotemcel), for the Treatment of Sickle Cell Disease and Transfusion-Dependent Beta Thalassemia. Retrieved September 27, 2024, from https://www.biospace.com/press-releases/health-canada-grants-marketing-authorization-of-first-crispr-cas9-gene-edited-therapy-casgevy-exagamglogene-autotemcel-for-the-treatment-of-sickle-cell-disease-and-transfusion-dependent-beta-thalassemia [2] Capricor Therapeutics Announces Intent to File Biologics License Application for Full Approval of Deramiocel for the Treatment of Duchenne Muscular Dystrophy Cardiomyopathy. Retrieved September 24, 2024, from https://www.capricor.com/investors/news-events/press-releases/detail/291/capricor-therapeutics-announces-intent-to-file-biologics [3] Immusoft to Announce Positive Phase 1 Data for First Engineered B Cell Therapy in a Clinical Trial. Retrieved September 23, 2024 from https://www.prnewswire.com/news-releases/immusoft-to-announce-positive-phase-1-data-for-first-engineered-b-cell-therapy-in-a-clinical-trial-302255551.html [4] KSQ Therapeutics Announces FDA Clearance of IND Application for KSQ-004EX, a CRISPR/Cas9 Engineered Tumor-Infiltrating Lymphocyte (eTIL®) Therapy. Retrieved September 27, 2024, from https://www.globenewswire.com/news-release/2024/09/24/2952011/0/en/KSQ-Therapeutics-Announces-FDA-Clearance-of-IND-Application-for-KSQ-004EX-a-CRISPR-Cas9-Engineered-Tumor-Infiltrating-Lymphocyte-eTIL-Therapy.html#:~:text=KSQ-004EX,%20an%20eTIL%20%C2%AE%20cell%20therapy [5] Minovia Therapeutics Announces FDA Clearance of IND Application for a Phase Ib Clinical Trial of MNV-201 in Low Risk Myelodysplastic Syndrome. Retrieved September 27, 2024, from https://www.globenewswire.com/news-release/2024/09/26/2954055/0/en/Minovia-Therapeutics-Announces-FDA-Clearance-of-IND-Application-for-a-Phase-Ib-Clinical-Trial-of-MNV-201-in-Low-Risk-Myelodysplastic-Syndrome.html [6] 中国国家药监局药品审评中心官网. Retrieved September 26, 2024, from https://www.cde.org.cn/main/xxgk/listpage/da6efd086c099b7fc949121166f0130c [7] Shusen Wang et al., (2024) Transplantation of chemically induced pluripotent stem-cell-derived islet under the abdominal anterior rectus sheath in a type 1 diabetes patient, Cell Doi: https://doi.org/10.1016/j.cell.2024.09.004 [8] 深耕CGT赛道 | 精准生物首个自身免疫疾病CAR-T疗法IND申请获受理. Retrieved September 27, 2024, from https://mp.weixin.qq.com/s/H9vJ7KIRXN_kFCOKuwpmtQ [9] Genespire raises €46.6 million (~$52 million) in a Series B round to advance its first pediatric in-vivo gene therapy into the clinic. Retrieved September 25, 2024, from https://www.genespire.com/wp-content/uploads/2024/09/240925-Genespire-Series-B-press-release-FINAL.pdf [10] 公司动态 | 星赛瑞真完成数千万元天使轮融资，天使+轮融资火热进行中！Retrieved September 27, 2024, from https://mp.weixin.qq.com/s/Ch7Ex7HjTSL0OGyaBxYkJg [11] 信念医药与AskBio达成战略合作共同探索创新基因疗法潜力. Retrieved September 27, 2024, from https://mp.weixin.qq.com/s/ajt06l5MDxV2jR_RMqo1wA 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

基因疗法上市批准临床1期孤儿药细胞疗法

2024-09-24

·GlobeNewswire-Health Care

KSQ Therapeutics Announces FDA Clearance of IND Application for KSQ-004EX, a CRISPR/Cas9 Engineered Tumor-Infiltrating Lymphocyte (eTIL®) Therapy

Phase 1/2 clinical study will evaluate the safety and preliminary efficacy of KSQ-004EX in advanced solid tumorsLEXINGTON, Mass., Sept. 24, 2024 (GLOBE NEWSWIRE) -- KSQ Therapeutics, Inc. (KSQ), a clinical-stage biotechnology company developing novel treatments for solid tumors, in collaboration with The University of Texas MD Anderson Cancer Center (MD Anderson) and the Cell Therapy Manufacturing Center (CTMC), today announced that the U.S. Food and Drug Administration (FDA) has cleared an Investigational New Drug (IND) application for a Phase 1/2 clinical study of KSQ-004EX, KSQ’s second engineered tumor-infiltrating lymphocyte (eTIL®) program. KSQ-004EX consists of TIL in which the genes encoding SOCS1 and Regnase-1 are inactivated using CRISPR/Cas9 gene editing. KSQ’s CRISPRomics® platform identified SOCS1 and Regnase-1 as key regulators of anti-tumor potency and persistence of TIL in preclinical models, providing KSQ-004EX with best-in-class potential in the treatment of advanced solid tumor indications. “As we continue to learn more about the biology of our eTIL candidates, we gain confidence that they can redefine the treatment of solid tumors, including difficult-to-treat cancers. We’re excited to bring an additional therapy into the clinic with the experts at MD Anderson, where this study will be initiated,” said Qasim Rizvi, Chief Executive Officer of KSQ. “Solid tumor treatment continues to be a significant challenge in oncology. The ability to offer patients a novel cell therapy is encouraging,” said Rodabe Amaria, M.D., professor of Melanoma Medical Oncology at MD Anderson and principal investigator of the KSQ-004EX study. “The preclinical KSQ-004EX data is promising, and we look forward to exploring the potential of KSQ’s dual-edited TIL.” Phase 1/2 Trial Design The Phase 1/2 clinical trial is an open-label, dose-escalation study for patients with select advanced solid tumors. The primary objective of the Phase 1 portion of the trial is to evaluate the safety and tolerability of KSQ-004EX. The primary objective of Phase 2 is to evaluate anti-tumor activity in multiple indication-specific cohorts. About KSQ-004EX KSQ-004EX, an eTIL® cell therapy in which TIL are edited to inactivate the genes encoding SOCS1 and Regnase-1, has the potential to revolutionize the treatment of solid tumors. In preclinical studies, KSQ-004EX demonstrated enhanced anti-tumor function in solid tumor models refractory to PD-1 inhibition. KSQ-004EX is manufactured by CTMC using KSQ’s ExPRESS™ process using patient tumor samples, including core biopsies, as starting material. About KSQ Therapeutics KSQ Therapeutics is advancing a pipeline of tumor- and immune-focused drug candidates to treat cancer across multiple drug modalities, including targeted therapies, adoptive cell therapies, and immunotherapies. KSQ's proprietary CRISPRomics® discovery engine enables genome-scale, in vivo validated, unbiased target discovery across broad therapeutic areas. For more information, please visit www.ksqtx.com and follow us on LinkedIn and X. KSQ Media Contact: Cory Trombleecory@scientpr.com

细胞疗法临床申请免疫疗法临床2期临床1期

2024-08-28

·生物探索

Science丨调控II型免疫反应中GATA3的关键因子

引言 II型免疫反应在维持组织稳态和提供保护性免疫反应方面发挥着至关重要的作用，特别是在组织修复、过敏性疾病和抗寄生虫免疫中。II型免疫反应的主要效应细胞包括先天淋巴细胞ILCs和适应性T辅助细胞（Th2细胞），这些细胞的生成和功能依赖于转录因子GATA3。GATA3在ILC2s和Th2细胞中的表达进一步上调，驱动II型免疫反应。然而，GATA3这种关键调控因子的上调机制尚不完全清楚，这限制了对II型免疫反应在健康和疾病中的作用的理解。 GATA3的调控对于维持II型免疫反应的动态平衡至关重要。虽然GATA3被认为是Th2细胞和ILC2s的“主控”调节因子，但它也是所有ILC家族成员和所有T细胞发育所必需的。因此，在未激活的状态下维持适度的GATA3表达，而在需要时上调以支持II型免疫反应，是一个复杂且高度受控的过程。特别是，在应对细菌、病毒和真菌感染时，GATA3需要保持在较低水平，以避免抑制I型和III型免疫反应。来自英国剑桥MRC分子生物学实验室Andrew N. J. McKenzie 团队在Science上发表题为Mef2d potentiates type-2 immune responses and allergic lung inflammation 的文章。本文通过筛选发现Mef2d是II型免疫反应中的关键调控因子，通过抑制Regnase-1的表达，增强了ILC2对IL-33的响应，进而促进GATA3和IL-13的表达。作者使用CRISPR-Cas9筛选技术，通过转基因小鼠模型对GATA3和IL-13的调控因子进行筛选。作者首先将sgRNA文库转导至来源于报告基因小鼠的普通淋巴前体细胞，随后通过流式细胞术对ILC2s的发育和分化进行分析。筛选结果显示，Mef2d是GATA3和IL-13的关键调控因子。进一步的分析验证了Mef2d在ILC2s中的表达与GATA3的上调和IL-13的分泌密切相关。作者通过生成Mef2d缺失小鼠（Il7rCreMef2df/f），研究Mef2d在II型免疫反应中的作用。作者对Mef2d缺失小鼠和对照小鼠进行不同免疫应激处理，如IL-33和Alternaria alternata过敏原的鼻内给药，随后评估肺部ILC2s、Th2细胞及相关免疫细胞的数量和功能。结果显示Mef2d缺失小鼠在IL-33和Alternaria alternata刺激下，表现出显著减少的ILC2s和Th2细胞数量，以及降低的GATA3和IL-13表达水平。此外，Mef2d缺失小鼠的肺部嗜酸性粒细胞和M2巨噬细胞数量也明显减少，显示出其在II型免疫反应中的重要性。为研究Mef2d的具体调控机制，作者进行了RNA-seq和ChIP-seq分析，以比较调控小鼠和Mef2d缺失小鼠ILC2s的基因表达和染色质状态。此外，通过共培养和基因敲除实验，进一步验证Mef2d对Regnase-1的调控作用。RNA-seq和ChIP-seq分析显示，Mef2d通过结合Zc3h12a基因（编码Regnase-1）附近的DNA序列，抑制Regnase-1的表达，从而减少GATA3 mRNA的降解，增强ILC2s对IL-33的响应，增加ST2和IL-13的表达水平。共培养和基因敲除实验进一步验证了这一调控机制。作者评估了不同组织中Mef2d缺失对ILC2表型的影响，特别是在肺、脂肪组织、骨髓和肠道中，通过流式细胞术分析GATA3和ST2的表达水平。结果显示，Mef2d缺失导致肺、脂肪组织和骨髓中的ILC2s表达ST2水平显著降低，而肠道ILC2s受影响较小。这表明Mef2d在不同组织中的作用具有一定的特异性，主要影响依赖ST2的ILC2s。本研究证明了Mef2d是II型免疫反应中的关键调控因子，通过抑制Regnase-1的表达，增强了ILC2对IL-33的响应，进而促进GATA3和IL-13的表达。本研究为进一步理解II型免疫反应的复杂调控机制提供了新的视角，同时也为开发针对过敏性疾病的新型治疗策略奠定了基础。参考文献 http://doi.org/10.1126/science.adl0370 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

基因疗法临床结果免疫疗法