Bronchopulmonary Dysplasia (BPD) is a multi-factorial disease process that is the end result of an immature, surfactant deficient lung that has been exposed to hyperoxia, mechanical ventilation and infection. These conditions initiate an inflammatory response characterized by elevated inflammatory cell infiltrates and proinflammatory cytokines that lead to the development of significant acute and chronic lung injury.
The study drug, rhCC10, is a recombinant version of natural human CC10 protein. Native CC10 is produced primarily by non-ciliated respiratory epithelial cells, called Clara cells and is the most abundant protein in the mucosal fluids in normal healthy lungs.
The purpose of this study is to evaluate the pharmacokinetics, safety, tolerability and anti-inflammatory effects of a single intratracheal (IT) dose of rhCC10 to intubated premature infants receiving positive pressure ventilation for treatment of respiratory distress syndrome (RDS) to prevent long term respiratory complications referred to as bronchopulmonary dysplasia, and, more recently, as Chronic Pulmonary Insufficiency of Prematurity (CPIP; asthma, cough, wheezing, multiple respiratory infections).
CC10 regulates inflammatory responses and protects the structural integrity of pulmonary tissue while preserving pulmonary mechanical function during various insults (eg. viral infection, bacterial endotoxin, ozone, allergens, hyperoxia). Together these properties suggest that administration of rhCC10 may help to facilitate development of normal airway epithelia and prevent the inflammation that leads to CPIP in these infants.
This study is funded by the FDA Office of Orphan Product Development (OOPD).

开始日期2013-10-01

申办/合作机构

Tufts Medical Center, Inc.

[+5]

NCT01473264 / Completed临床1/2期

Safety and Tolerability of Recombinant Human Clara Cell 10kDa Protein (rhCC10) Delivered Intratracheally to Premature Neonates With Respiratory Distress Syndrome

Bronchopulmonary Dysplasia (BPD) is a multi-factorial disease process that is the end result of an immature, surfactant deficient lung that has been exposed to hyperoxia, mechanical ventilation and infection. These conditions initiate an inflammatory response characterized by elevated inflammatory cell infiltrates and proinflammatory cytokines that lead to the development of significant acute and chronic lung injury.
The study drug, rhCC10, is a recombinant version of natural human CC10 protein. Native CC10 is produced primarily by non-ciliated respiratory epithelial cells, called Clara cells and is the most abundant protein in the mucosal fluids in normal healthy lungs.
The purpose of this study was to evaluate the pharmacokinetics, safety, tolerability and anti-inflammatory effects of a single intratracheal (IT) dose of rhCC10 to intubated premature infants receiving positive pressure ventilation for treatment of respiratory distress syndrome (RDS) to prevent long term respiratory complications referred to as bronchopulmonary dysplasia, and, more recently, as chronic respiratory morbidity (CRM; asthma, cough, wheezing, multiple respiratory infections).
CC10 regulates inflammatory responses and protects the structural integrity of pulmonary tissue while preserving pulmonary mechanical function during various insults (eg. viral infection, bacterial endotoxin, ozone, allergens, hyperoxia). Together these properties suggest that administration of rhCC10 may help to facilitate development of normal airway epithelia and prevent the inflammation that leads to CRM in these infants.

开始日期2000-01-01

申办/合作机构

Therabron Therapeutics, Inc.

[+1]

100 项与 Uteroglobin 相关的临床结果

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100 项与 Uteroglobin 相关的转化医学

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100 项与 Uteroglobin 相关的专利（医药）

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235

项与 Uteroglobin 相关的文献（医药）

2023-12-21·Journal of biomolecular structure & dynamics

A cystatin C similar protein from Musa acuminata that inhibits cathepsin B involved in rheumatoid arthritis using in silico approach and in vitro cathepsin B inhibition by protein extract

Article

作者: Chakraborty, Rajkumar ; Aggarwal, Kamal Krishan ; Hasija, Yasha ; Rangra, Sabita

Rheumatoid arthritis (RA) is an auto-immune disease that affects the synovial lining of the joints, causes synovitis and culminates to joint destruction. Cathepsin B is responsible for digesting unwanted proteins in extracellular matrix but its hyper expression could implicate in pathological diseases like RA. Available treatments for RA are classified into non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs), and steroids, but the severe side effects associated with these drugs is one of concerns and cannot be ignored. Thus, any alternative therapy with minimum or no side effects would be a cornerstone. In our in silico studies a cystatin C similar protein (CCSP) has been identified from Musa acuminata that could effectively inhibit the cathepsin B activity. In silico and molecular dynamics studies showed that the identified CCSP and cathepsin B complex has binding energy -66.89 kcal/mol as compared to cystatin C - cathepsin B complex with binding energy of -23.38 kcal/mol. These results indicate that CCSP from Musa acuminata has better affinity towards cathepsin B as compared to its natural inhibitor cystatin C. Hence, CCSP may be suggested as an alternative therapeutic in combating RA by inhibiting its one of the key proteases cathepsin B. Further, in vitro experiments with fractionated protein extracts from Musa sp. peel inhibited cathepsin B to 98.30% at 300 µg protein concentration and its IC₅₀ was found to be 45.92 µg indicating the presence of cathepsin B inhibitor(s) in protein extract of peel which was further confirmed by reverse zymography.Communicated by Ramaswamy H. Sarma.

2023-11-01·Microfluidics and nanofluidics

Lab on a chip for detecting Clara cell protein 16 (CC16) for potential screening of the workers exposed to respirable silica aerosol

Article

作者: Ku, Bon Ki ; Ghosh, Sthitodhi ; Ahn, Chong ; Lee, Jong Seong ; Lee, Taekhee ; Upaassana, V Thiyagarajan ; Shin, Jae Hoon

Early detection of pulmonary responses to silica aerosol exposure, such as lung inflammation as well as early identification of silicosis initiation, is of great importance in disease prevention of workers. In this study, to early screen the health condition of the workers who are exposed to respirable silica dusts, an immunoassay lab on a chip (LOC) was designed, developed and fully characterized for analyzing Clara cell protein 16 (CC16) in serum which has been considered as one of the potential biomarkers of lung inflammation or lung damage due to the respirable silica dusts. Sandwich immunoassay of CC16 was performed on the LOC developed with a custom-designed portable analyzer using artificial serums spiked with CC16 protein first and then human serums obtained from the coal mine workers exposed to the respirable silica-containing dusts. The dynamic range of CC16 assay performed on the LOC was in a range of 0.625-20 ng/mL, and the achieved limit of detection (LOD) was around 0.35 ng/mL. The assay results of CC16 achieved from both the developed LOC and the conventional 96 well plate showed a reasonable corelation. The correlation between the conventional reader and the developed portable analyzer was found to be reasonable, resulting in R² ~ 0.93. This study shows that the LOC developed for the early detection of CC16 can be potentially applied for the development of a field-deployable point-of-care testing (POCT) for the early monitoring of the field workers who are exposed to silica aerosol.

2023-06-01·Journal of hazardous materials

Relationship between systemic inflammation and lung injury induced by chromate exposure: A cross–sectional study in workers

Article

作者: Yuan, Fang ; Zhang, Qiaojian ; Hu, Guiping ; Zhu, Xiaojun ; Yu, Shanfa ; Jia, Guang ; Wang, Tiancheng ; Hong, Shiyi ; Zhang, Yali ; Su, Zekang

Hexavalent chromium [Cr(VI)] compounds, known as "Group I Human Carcinogen" and "Category I Respiratory Sensitizer", posed great challenges to the respiratory system. A cross-sectional study was undertaken among chromate workers. Serum club cell protein 16 (CC16) and soluble urokinase-type plasminogen activator receptor (suPAR) were measured using ELISA. Thirteen macrophage-related mediators were tested using cytometric bead array. After controlling for sex, age, smoking status, drinking status and BMI, each increase of one-unit of Ln-transformed blood Cr was related to the increase of IL-1beta [Beta (95% CI), 7.22(1.14, 13.29)%, P = 0.021], IL-23 [8.5(1.15, 15.85)%, P = 0.021], IFN-gamma [3.14(0.15, 6.13)%, P = 0.040], and suPAR [9.31(2.5, 16.12) %, P = 0.008], as well as the increase of CC16 by 3.88(0.42, 7.34) % (P = 0.029). Moreover, these inflammatory mediators played an mediation role in the rise of CC16 caused by Cr(VI). The exposure-response curve analysis revealed a substantial nonlinear association of IFN-gamma and suPAR with CC16, thus the mediation effect of INF-gamma and suPAR required cautious interpretation. The positive connection between macrophage-related mediators was stronger in the high exposure group than in the low exposure group, suggesting that high concentration of chromate might promote a complex interplay within the immune system.

项与 Uteroglobin 相关的新闻（医药）

2023-04-06

·生物谷

李博文等开发新型LNP载体，吸入后可实现对肺部的高效mRNA递送及基因编辑

利用高通量平台，研究团队合成和筛选了可生物降解的可电离脂质组合文库，以构建用于递送mRNA和CRISPR-Cas9基因编辑器的吸入式递送载体。先天性肺部疾病，例如表面活性蛋白缺乏症、囊性纤维化、α-1抗胰蛋白酶缺乏症等等，会导致终身发病甚至是死亡。虽然这些疾病的遗传机制已经被深入研究，但仍然缺乏有效的治疗方案。最近，可吸入式mRNA递送平台备受制药业和学术界的关注。这种平台可以提供非侵入性、直接进入肺上皮细胞和肺泡的RNA药物，在应用于囊性纤维化、特发性肺纤维化、肺癌和肺部感染等多种肺部疾病治疗方面有巨大潜力。以CRISPR-Cas9为代表的基因编辑工具，通过气管内递送到肺部细胞，是一种极具潜力的治疗先天性肺部疾病的方法。目前，已经使用腺相关病毒（AAV）在人体内进行了基因编辑治疗。然而，AAV载体递送Cas9的DNA在体内的长期表达，虽然提高了成功编辑的效率，但也会导致脱靶编辑的积累。此外，AAV衣壳的免疫原性限制了其重复给药，更重要的是，AAV载体容量有限（不超过4.7kb），这导致其难以递送编辑效率更高的spCas9。而AAV病毒载体面临的这些挑战和限制，可以通过非病毒载体来递送mRNA来解决，从而实现短暂表达和重复给药，而且能够突破载体容量限制。脂质纳米颗粒（LNP）是目前临床试最先进的非病毒载体，随着在新冠mRNA上的成功应用而被广泛接受，在临床试验中，LNP递送的Cas9 mRNA实现了肝脏遗传疾病的有效治疗。然而，目前还没能通过吸入的方式利用LNP递送系统在体内进行高效的肺部基因编辑。与肝脏相比，肺部特殊的细胞类型、粘液屏障和粘液纤毛清除系统对吸入递送提出了独特的挑战。此外，相比于mRNA疫苗，基于mRNA的基因编辑对LNP的递送效率要求更高。 2023年3月，加拿大核酸疫苗与治疗研究主任（Canada Research Chair），多伦多大学药学院助理教授李博文联合麻省理工学院教授 Robert Langer、Daniel Anderson 和麻省大学医学院教授高光坪，薛文等人在 Nature Biotechnology 期刊发表了题为：Combinatorial design of nanoparticles for pulmonary mRNA delivery and genome editing（用于肺部mRNA递送和基因组编辑的纳米颗粒的组合设计）的研究论文，并与负责该论文审阅的编辑团队和专家以Research Briefing形式对其主要研究结果共同进行了总结和展望：First lipid nanoparticle-enabled gene editing in the lung via inhalation。利用高通量平台，研究团队合成和筛选了可生物降解的可电离脂质组合文库，以构建用于递送mRNA和CRISPR-Cas9基因编辑器的吸入式递送载体。并从中筛选和鉴定了RCB-4-8 LNP，这种领先的脂质纳米颗粒（LNP）具有更好的生物可降解性和安全性，可重复气管内给药。它提供了全球首个成功利用LNP实现高效肺上皮细胞基因编辑的方法，为先天性肺部疾病的基因治疗开辟了新的途径。在这项研究中，研究团队设计了一个三组分反应（3-CR）体系，其中硝基蓖麻油酸丙烯酸酯（NRA）连接剂与脂肪醇（脂质尾）偶联，然后与含有伯胺、仲胺或叔胺的头部基团连接。与传统的将胺类头部基团直接与脂质尾结合的双组分反应相比，该三组分反应（3-CR）体系简化了繁琐的合成过程，增加了脂质结构多样性，快速生成了结构多样化的生物可降解电离脂质组合库。研究团队合成了一个包含新的720种不同脂质的文库，由10个不同长度脂质尾和72个不同头部基团通过NRA连接子连接构成。该脂质文库中所有的可电离脂质都含有大量的酯类和碳酸盐基团，以提高可电离脂类的生物降解性，这有助于减少潜在不良反应，增强了与多剂量方案的兼容性。通过体内动物实验和体外细胞实验的筛选，研究团队发现，RCB-4-8 LNP在体内显示出对肺部最高的转染效率（递送Luciferase荧光素酶的mRNA），并在体外显示出最高的基因敲除效率（递送CRISPR-Cas9系统mRNA组分）。之前的研究显示，使用阳离子脂质DOTAP替代DOPE，可有效提高全身给药后LNP在肺部的转染效果。在这项最新研究中，研究团队使用DOTAP重新配置了RCB-4-8 LNP，结果显示，其气管内给药递送Luciferase荧光素酶的mRNA后在肺部表达效率得到了进一步改善，这可能是新的阳离子脂质组成可以增强LNP的肺细胞内化和粘液驻留。此外，与直接使用移液管混合的LNP配置方式相比，通过微流控技术产生的LNP具有更小的尺寸，更低的聚合物分散性指数（PDI）和更高的封装效率。进一步的剂量反应实验显示，相比FDA已批准的MC3-LNP（为Alnylam公司2018年获批RNA药物ONPATTRO®中所使用的LNP），RCB-4-8 LNP对肺部的转染效率提高了约100倍，相比近期开发的一款靶向肺部的新型LNP【2】，RCB-4-8 LNP对肺部的转染效率提高了10倍以上。此外，在给药48小时后，RCB-4-8 LNP在肺中保留量<30%，而MC3-LNP则>90%，这表明表明RCB-4-8 LNP的潜在毒性较低。接下来，研究团队在Ai9 tdTomato小鼠模型中检验了RCB-4-8 LNP递送Cre重组酶mRNA（Cre-mRNA）介导的体内基因编辑的效果，结果显示，RCB-4-8 LNP递送的Cre-mRNA在气道中实现了良好的基因编辑效果，而且，三次给药进一步增加了基因编辑效果，这表明RCB-4-8 LNP可以重复给药，这与现在常用的AAV病毒载体相比是一个非常显著的优势。同时研究表明，RCB-4-8对纤毛上皮细胞（a-Tubulin+）和Club上皮细胞（CCSP+），这两种先天性肺部疾病的主要发病细胞，都可以实现高效的基因编辑。接下来，研究团队在Ai9 tdTomato小鼠模型中探索了使用RCB-4-8 LNP向肺部递送CRISPR-Cas9组分的可行性。不同剂量的LNP与AAV5递送相比，高剂量RCB-4-8 LNP递送Cas9 mRNA后编辑效率与最近报道的双AAV载体介导的Cas9的编辑效率相当。而LNP递送mRNA的瞬时性能够避免AAV递送Cas9的长期表达带来的脱靶性等潜在风险。总的来说，这些令人信服的实验结果证明了RCB-4-8 LNP在肺中实现CRISPR-Cas9基因编辑方面的巨大潜力。综上所述，该研究合成并评估了一个可生物降解的可电离脂质文库，其中RCB-4-8 LNP被鉴定为能够实现高效的肺部mRNA递送和基因编辑。与基于AAV病毒的DNA递送系统相比，LNP递送mRNA的半衰期相对较短，从而减少了Cas9长期表达积累脱靶效应的潜在风险。此外，与AAV病毒载体不同的是，LNP可以重复给药，这对于在肺部达到治疗性基因编辑水平可能是至关重要的。与mRNA疫苗相比，基于mRNA的治疗药物和基因编辑的发展路径面临额外的挑战。免疫接种只需要产生最少量的蛋白质，因为免疫系统可以通过细胞介导和抗体介导的免疫反应显著放大抗原信号。相比之下，mRNA治疗需要高达1000倍的蛋白质水平才能达到治疗阈值【3】。此外，mRNA治疗还需要作用于特定的靶通路、细胞、组织或器官，这对其递送系统提出了更高的要求。该研究已经证明了RCB-4-8 LNP的高效性，该纳米颗粒可以将CRISPR-Cas9系统以mRNA形式高效递送到肺中的纤毛上皮细胞和Club上皮细胞，证明了将mRNA用于治疗各种肺部疾病，包括囊性肺纤维化（CF）的基因编辑治疗的可行性和巨大潜力。 Nature Biotechnology 同期还配发了来自以色列特拉维夫大学的 Dan Peer 教授的题为：CRISPR editing in the lung with novel lipids 的“新闻与观点”文章。 Dan Peer 教授指出，李博文等人使用改进的脂质纳米颗粒（LNP）通过吸入式递送可以在小鼠肺部细胞进行CRISPR基因编辑，这种方法有助于开发有效治疗肺部疾病的基因编辑药物，通过进一步优化，推动mRNA技术的临床应用。他还表示，与传统疫苗和疗法相比，该mRNA-LNP平台具有几项明显优势，包括无细胞体系、可快速生产、高通用性，以及良好的安全性。

基因疗法信使RNA疫苗临床结果核酸药物

2022-12-30

·生物谷

Int. J. Biol. Sci: HIF-1α/SCD1轴可能成为肺癌治疗的新靶点

肺癌的发病率仅次于乳腺癌，是癌症相关死亡的主要原因；2020年估计有180万人死于肺癌。研究表明，癌症的行为由癌细胞和肿瘤微环境共同决定。肺癌的发病率仅次于乳腺癌，是癌症相关死亡的主要原因；2020年估计有180万人死于肺癌。研究表明，癌症的行为由癌细胞和肿瘤微环境共同决定。肿瘤相关成纤维细胞(CAF)是TME的重要组成部分，高表达多种蛋白，如α-平滑肌肌动蛋白(α-SMA)、成纤维细胞激活蛋白(FAP)、胶原α-2(I)链(COL1A2)和足阳素(PDPN)。肿瘤相关成纤维细胞(CAF)是肿瘤微环境(TME)中的主要成分，促进肺癌的进展。已有研究报道，代谢重编程可以调节CAF的功能，尤其是脂代谢异常。脂滴是一种普遍存在的细胞器，储存中性脂类，在脂类代谢中起着至关重要的作用。然而，关于LDS在肺CAF中的合成和功能知之甚少。图片来源：https://pubmed-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/36439884/ 近日，来自郑州大学附属第一医院的研究者们在Int. J. Biol. Sci杂志上发表了题为“Stearoyl-CoA Desaturase-1 dependent lipid droplets accumulation in cancer-associated fibroblasts facilitates the progression of lung cancer”的文章，该研究揭示了HIF-1α/SCD1轴调控低密度脂蛋白在CAF中的积聚，可能成为肺癌治疗的新靶点。研究者采用TETO-EGFRL858R；CCSP-RTTA转基因小鼠模型建立自发性肺肿瘤模型，观察LDS在CAF中的蓄积。用小鼠成纤维细胞系体外研究LDS积聚对成纤维细胞表型变化的影响。另外，研究者采用RNA测序、Western blotting、RT-PCR和DNA下拉等方法研究成纤维细胞LDS合成的机制。研究者发现LDS在肺CAF中丰富，并诱导CAF的亲肿瘤表型，并增加α-平滑肌肌动蛋白(α-SMA)和胶原α2(I)链(COL1A2)的表达。作为主要调节因子，缺氧诱导因子-1α(HIF-1α)在活化的成纤维细胞中高表达，并增加乳酸脱氢酶的含量。测序结果表明，硬脂酰辅酶A脱氢酶1(Scd1)是HIF-1α的下游基因，可上调成纤维细胞中LDs的数量。重要的是，抑制SCD1减少了肺癌的生长，这与CAF中LDS的减少有关。人肺腺癌组织芯片分析显示，高表达SCD1CAF与HIF-1α表达呈正相关，且肺癌患者预后不良。肺CAF中低密度脂蛋白的蓄积图片来源：https://pubmed-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/36439884/ 综上所述，本研究结果证实了HIF-1α是成纤维细胞脂代谢的主要调节者，增加了LDs的丰度，并导致了肺成纤维细胞的肿瘤促进表型。该信号通路受HIF-1α/SCD1轴的调控。因此，HIF-1α/SCD1轴代表了肺癌治疗的潜在治疗靶点，以及脂代谢途径的其他组成部分。这一发现可能对肺癌的治疗靶向和预后标志物的开发具有重要意义。（生物谷 Bioon.com）参考文献 Yana Zhang et al. Stearoyl-CoA Desaturase-1 dependent lipid droplets accumulation in cancer-associated fibroblasts facilitates the progression of lung cancer. Int J Biol Sci. 2022 Oct 18;18(16):6114-6128. doi: 10.7150/ijbs.74924.

临床研究临床结果

100 项与 Uteroglobin 相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
-	Uteroglobin	-	DB14880

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
支气管肺发育不良	临床2期	-	Tufts Medical Center, Inc.	-
支气管肺发育不良	临床2期	-	The Brigham & Women's Hospital, Inc.	-

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01941745 (CTgov)	临床2期	呼吸窘迫综合征 \| 早产 \| 新生儿呼吸窘迫综合征 ... 更多	88	Low Dose rhCC10 (Low Dose rhCC10)	鬱蓋積齋構鏇衊糧製選(繭襯淵鬱範顧壓選糧壓) = 膚夢膚鏇醖艱窪齋鬱繭鑰窪鹽膚壓淵願製築淵 (願鬱淵獵顧齋艱願廠餘, 鏇觸獵選鏇壓鹹膚夢觸 ~ 鏇艱糧鹽製淵憲範糧蓋)	-	2019-09-10
				High dose rhCC10 (High Dose rhCC10)	鬱蓋積齋構鏇衊糧製選(繭襯淵鬱範顧壓選糧壓) = 獵鹹襯遞醖網窪簾積願鑰窪鹽膚壓淵願製築淵 (願鬱淵獵顧齋艱願廠餘, 襯積艱範築憲構鬱選鏇 ~ 製觸製衊夢願廠窪範願)