Introduction: We investigated the potential of LPS (10–300 µg/rat) administered intratracheally (i.t.) to induce reproducible features of acute lung injury (ALI) and compared the pharmacological efficacy of anti-inflammatory glucocorticoids and antifibrotic drugs to reduce the disease. Additionally, we studied the time-dependent progression of ALI in this LPS rat model. Methods: We conducted (1) dose effect studies of LPS administered i.t. at 10, 30, 100, and 300 μg/rat on ALI at 4 h timepoint; (2) pharmacological interventions using i.t. fluticasone (100 and 300 μg/rat), i.t. pirfenidone (4,000 μg/rat), and peroral dexamethasone (1 mg/kg) at 4 h timepoint; (3) kinetic studies at 0, 2, 4, 6, 8, 10, and 24 h post-LPS challenge. Phenotype or pharmacological efficacy was assessed using predetermined ALI features such as pulmonary inflammation, edema, and inflammatory mediators. Results: All LPS doses induced a similar increase of inflammation, edema, and inflammatory mediators, e.g., IL6, IL1β, TNFα, and CINC-1. In pharmacological intervention studies, we showed fluticasone and dexamethasone ameliorated ALI by inhibiting inflammation (>60–80%), edema (>70–100%), and the increase of cytokines IL6, IL1β, and TNFα (≥70–90%). We also noticed some inhibition of CINC-1 (25–35%) and TIMP1 (57%) increase with fluticasone and dexamethasone. Conversely, pirfenidone failed to inhibit inflammation, edema, and mediators of inflammation. Last, in ALI kinetic studies, we observed progressive pulmonary inflammation and TIMP1 levels, which peaked at 6 h and remained elevated up to 24 h. Progressive pulmonary edema started between 2 and 4 h and was sustained at later timepoints. On average, levels of IL6 (peak at 6–8 h), IL1β (peak at 2–10 h), TNFα (peak at 2 h), CINC-1 (peak at 2–6 h), and TGFβ1 (peak at 8 h) were elevated between 2 and 10 h and declined toward 24 h post-LPS challenge. Conclusion: Our data show that 10 μg/rat LPS achieved a robust, profound, and reproducible experimental ALI phenotype. Glucocorticoids ameliorated key ALI features at the 4-h timepoint, but the antifibrotic pirfenidone failed. Progressive inflammation and sustained pulmonary edema were present up to 24 h, whereas levels of inflammatory mediators were dynamic during ALI progression. This study’s data might be helpful in designing appropriate experiments to test the potential of new therapeutics to cure ALI.

2023-03-01·Physiological Reports

Characterization of acute lung injury in the bleomycin rat model

Article

作者: Kadam, Anil Hari ; Schnitzer, Jan E

AbstractThe aim of this study was to describe and characterize the pathophysiological changes occurring during the early inflammatory phase (first 3 days) in the rat bleomycin model of lung injury preceding the development of fibrosis. Further, we wanted to understand the kinetics and factors contributing to bleomycin‐induced acute lung injury (ALI) and provide a robust, reliable and reproducible framework of features of ALI readouts to assess effects of therapeutics on bleomycin‐induced ALI in rats. We induced ALI in rats with intratracheal (i.t.) installation of bleomycin. The animals were sacrificed on predetermined time points, that is, Day 0, 1, 2, and 3 post the bleomycin challenge. We analyzed bronchoalveolar lavage fluid (BALF) and lung tissue to establish and assess relevant experimental features of ALI. We demonstrated that bleomycin induced key features of experimental ALI including a profound increase in neutrophils in BALF (50–60%), pulmonary edema, and lung pathology on Day 3 after challenge. Furthermore, we showed that TGF‐β1, IL‐1β, TNF‐α, IL‐6, CINC‐1, TIMP‐1, and WISP‐1 were induced by studying their kinetic profile during the first 3 days after bleomycin injury consistent with their known role ALI. We also confirmed that detectable fibrogenesis occurs at the earliest on Day 3 after injury based on collagen content, along with changes in the TGF‐β/Smad signaling pathway and increased expression of Galectin‐3, Vimentin, and Fibronectin in lung homogenate. Our report presents robust features and contributing mediators/factors to the pathology of bleomycin‐induced ALI in rats on Day 3. The kinetic data provide insights on the progression of ALI and a detailed understanding of early events before actual fibrosis development. This set of experimental endpoints is very appropriate and invaluable for efficacy testing of potential novel therapeutic treatments (single or combined) in ALI and understanding their mechanism of action.

2023-01-01·Medical Research Archives

State Government Policy Responses to the COVID-19 Pandemic in the United States 2020-2022: Concordant Heterogeneity?

Article

作者: Koziol, James A ; Schnitzer, Jan E

Objectives. We investigate governmental responses to the COVID-19 pandemic on a statewide basis between January 2020 and June 2022, together with mortality rates attributable to COVID-19 over the same period. Our aim is to demarcate the states’ responses, and examine whether these differential responses are associated with COVID-19 mortality. Methods. Our study is based on individual state data from the Oxford COVID-19 Government Response Tracker, OxCGRT. We focus on the Government Response Index, the most comprehensive index tracked in the OxCGRT dataset. We use multivariate techniques to group the states into clusters relative to their similarities on the Government Response Index, and determine mortality rates attributable to COVID-19 in the individual groups. Results. We find that the Government Response Index was sustained at relatively constant levels in the states, with two major transition periods: a rapid rise in stringency during April through June of 2020, and a gradual decline in May and June of 2021. Heterogeneity in the Government Response Index dramatically increased in 2022. No consistent patterns emerge when relating government stringency measures with COVID-19 mortality rates. Conclusions. There is inconsistent evidence that increased governmental stringency is associated with lower COVID-19 mortality; judicious selection of time frames can lead to contrasting inferences. Political trends and motivations appear to have an outsized influence on governmental responses to the COVID-19 public health crisis, to the detriment of the populace.

项与 Proteogenomics Research Institute for Systems Medicine 相关的新闻（医药）

2024-07-05

·创鉴汇

上半年亚太日、澳、韩28家创新药公司获融资！

▎药明康德内容团队编辑回顾上半年，日本、澳大利亚及韩国这三个亚太国家有众多生物制药公司获得融资，这些资金将持续促进三国创新药研发技术的发展及推动全球新药管线的多元化。据创鉴汇不完全统计，今年上半年三国共有28家生物制药公司获得融资，已披露融资总额超2亿美元。其中，值得关注的亮点包括：早期融资为主：早期融资（B轮及以前）事件占比近68%；共有6家企业获B轮融资，总融资额达8100万美元；7家企业获得A轮融资，总金额达5300万美元；6家初创企业获得种子轮融资，总金额达1245万美元。日本、韩国企业融资活跃：获融资公司中，各有12家企业总部位于日本或韩国。肿瘤仍受较高关注度：至少12家公司研发疾病领域包括肿瘤相关疾病，其中值得关注的有癌症小分子靶向药开发公司Idience、癌症药物研发公司DAAN BioTherapeutics等。 Aravax完成B轮融资，总额共计4220万美元 Aravax成立于2015年，由Alfred Health和莫纳什大学学术转化而来，并由Brandon Capital Partners管理的医学研究商业化基金(MCRF)早期投资建立。公司使用专有技术精确地重置免疫系统以耐受过敏原，且不会在治疗期间引起过敏反应。 Aravax的主要产品管线PVX108是一种用于恢复花生的耐受性，并降低意外接触花生后发生严重过敏反应风险的安全、简单的治疗药物。由代表花生过敏原序列的多肽混合物组成，这些序列对花生特异性T细胞的识别至关重要。与其他花生过敏免疫疗法不同，PVX108不含引起严重过敏反应的花生蛋白。目前，PVX108正在澳大利亚和美国同步进行针对青少年和儿童治疗花生过敏的临床2期研究。今年1月，公司完成了第二笔B轮融资，本次融资金额2220万美元，将用于其花生过敏药物2期临床研究。自2022年12月，Aravax B轮融资总金额共计4220万美元。 Orizuru Therapeutics完成33亿日元B轮融资 Orizuru Therapeutics成立于2021年，由武田制药和京都大学学术成果转化而来。公司以研发为导向，旨在开发诱导多能干细胞（iPSCs）用于治疗大量未满足需求的危及生命的疾病。目前的重点业务包括：1.通过细胞疗法开发再生医疗产品和2.提供iPSCs相关专业服务以支持药物发现研究。公司目前用于两款核心产品管线OZTx-410和OZTx-556。OZTx-410是一种基于公司专有技术开发的iPSC衍生的胰岛细胞产品。OZTx-410含有安全、高纯度的胰腺内分泌细胞聚集体，有望在葡萄糖负荷和低血糖反应中表现出生理性胰岛素分泌。目前公司计划启动其临床试验以探究其长期正常化血糖水平、改善严重1型糖尿病患者的生活质量的效果。OZTx-556是一种基于公司专有技术开发的iPSC衍生的心肌细胞产品。OZTx-556纯度高且具有对心脏的高植入能力，有望补充失去的心肌细胞并促进再肌肉化。目前公司计划开展其临床试验，旨在改善难以治疗的严重心力衰竭患者的心功能、身体功能和生活预后。今年2月，公司完成了33亿日元的B轮融资，将在加速细胞治疗业务，特别是临床开发和扩大生产中发挥关键作用。武田制药和京都大学作为投资方继续支持了本轮投资。 Prota Therapeutics完成2100万美元A1轮融资 Prota Therapeutics成立于2016年，是一家致力于开发和商业化尖端口服免疫疗法的生物技术公司。公司的专有食品免疫治疗技术由Mimi Tang教授研究团队学术成果转化而来。Tang教授是澳大利亚默多克儿童研究所（Murdoch Children’s Research Institute）过敏免疫学研究小组的负责人和过敏转化中心的主任，墨尔本大学儿科学系的教授研究员和墨尔本皇家儿童医院（Melbourne's Royal Children’s Hospital）的免疫学和过敏症专家顾问。 Prota Therapeutics正准备推进其临床项目，战略性计划启动一项关键3期研究以探索花生过敏治疗药物PRT120的疗效和安全性。今年1月，公司完成了2100万美元的A1轮融资，将助力PRT120的开发。 Idience获得250亿韩元战略投资 Idience成立于2019年，是一家专注于创新新药开发和商业化的生物制药公司，为韩国制药公司Ildong Holdings的子公司。公司拥有多种新型抗癌候选药物。其中核心药物Venadaparib是一种聚ADP核糖聚合酶（PARP）抑制剂，可阻止DNA单链断裂（SSB）的修复，并促进SSB向双链断裂（DSB）的转化，最终导致癌细胞的合成致死。Venadaparib目前正处于单药和与其他抗癌药物联用治疗多种实体瘤的临床试验阶段。2022年，该药获得了美国食品药品监督管理局（FDA）针对胃癌适应症的孤儿药资格认定（Orphan Drug Designation）。今年5月，公司获得了韩国制药公司Dong-a ST的250亿韩元的战略投资，使Dong-a ST成为其第二大股东。通过此次投资，Dong-a ST获得了共同开发以Venadaparib为基础的联合疗法的权利。 DAAN BioTherapeutics完成230亿韩元A轮融资 DAAN BioTherapeutics是一家开发免疫肿瘤药物综合研究平台，致力于研发细胞疗法、抗体和小分子抑制剂来治疗癌症；于2020年由延世大学医学院癌症中心Cho Byeong-cheol 教授创立。公司自主开发建立了TARGET平台，通过筛选新抗原、TAA（肿瘤相关抗原）和TSA（肿瘤特异性抗原）来发现靶点，基于平台技术提高了T细胞在癌细胞肿瘤微环境（TME）中的浸润能力、TME选择性和癌细胞特异性。基于细胞疗法和使用T细胞受体（TCR）的抗体疗法，公司开发了自体TCR-T候选药物DN-101，用于治疗EGFR L858R突变导致的肺癌。今年1月，公司完成了230亿韩元的A轮融资，本轮融资将用于其自体TCR-T候选药物DN-101的临床前和临床开发。 Avelos Therapeutics获得170亿韩元B轮融资 Avelos Therapeutics成立于2021年，专注于肿瘤药物的发现和开发，致力于在合成致死、DNA损伤反应和细胞周期领域研发不可成药靶点的小分子药物。目前公司已开发4条候选药物管线，其中核心管线AVS1001是一款MASTL激酶抑制剂候选药物，旨在影响细胞周期和DNA损伤反应。AVS1001在早前的临床前研究中显示出了选择性抑制癌细胞的优异疗效，预计今年下半年开启临床研究，拟针对结肠癌、胃癌、乳腺癌、卵巢癌、前列腺癌等多种癌症。今年5月，公司完成了170亿韩元的B轮融资，资金将用于核心管线AVS1001临床研究的启动。 GPN Vaccines完成1800万澳元的B轮融资 GPN Vaccines是一家临床阶段的生物技术公司，专注于肺炎链球菌疫苗的开发。公司基于专有的荚膜多糖缺乏肺炎链球菌工程菌株，通过伽马辐射灭活，产生全细胞肺炎球菌广谱疫苗。与其他灭活方式相比，伽马辐射灭活保持了表面蛋白抗原的结构，从而允许γ-PN诱导对细菌交叉反应蛋白抗原的广谱T细胞和B细胞免疫，有效地诱导保护性免疫。目前，新型肺炎球菌疫苗γ-PN已在澳大利亚完成了首次人体临床试验。今年6月，公司完成了计划1500万澳元的超额B轮融资，募集资金总额达1800万澳元，将助力γ-PN疫苗的临床验证。 PRISM BioLab完成15亿日元C轮融资新阶段 PRISM BioLab成立于2006年，由一群科学家基于他们的肽模拟小分子创新药技术而创立。公司利用其专有的PepMetics技术，设计和开发以蛋白质-蛋白质相互作用（PPI）为靶点的小分子抑制剂，致力于改变癌症，自身免疫性疾病，纤维化和其他疾病的患者的生活。PepMetics是一类独特的小分子，可模拟细胞内PPI交界和受体-配体相互作用中常见的α-螺旋和β-转角的三维结构。通过结合专有化学、PPI相关靶点的专业知识和人工智能支持，公司的PepMetics技术有望扩大药物发现领域，将“难以成药”的PPI转变为可小分子药物作用的靶点。经过十多年的研究和发展，公司已开发出临床药物管线和多个潜在候选药物化合物。今年1月，公司完成了新一阶段的C轮融资，共募集15亿日元，资金将用于改进PRISM的专有PepMetics化学平台、扩展生物学和筛选能力、推进PPI抑制剂管线进展。读者们请星标⭐创鉴汇，第一时间收到推送免责声明：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：本文由药明康德内容团队根据公开资料整理编辑，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发/复制至其他平台。转发授权请在「创鉴汇」微信公众号留言联系我们。更多数据内容推荐点击“在看”，分享创鉴汇健康新动态

免疫疗法临床2期细胞疗法

2024-04-25

·PRNewswire

PRISM BioLab, enters into a Joint Research and Licensing Agreement with Ono

PRISM BioLab will utilize PepMetics®, innovative small molecules that mimic three-dimensional structures of alpha-helix and beta-turns of peptides for drug discovery against oncology target selected by Ono TOKYO, April 25, 2024 /PRNewswire/ -- PRISM BioLab, Co. Ltd. ("PRISM"), a leading discovery and development biotechnology company designing small molecule inhibitors of protein-protein interaction (PPI) targets, today announced that it has entered into a target-exclusive research and licensing agreement with ONO PHARMACEUTICAL CO., LTD. ("Ono "). Under the terms of the agreement, Ono and PRISM will jointly create a development candidate for Ono's oncology target using PepMetics® technology. Upon identification of the development candidate, PRISM will license its rights to Ono for clinical development and commercialization. The deal includes upfront payments, pre-clinical, clinical and commercialization success-based milestones, royalties on future net sales, and other terms. Specific financial terms are not disclosed. "We highly appreciate PRISM's PepMetics® technology in PPI drug discovery", said Seishi Katsumata, Executive Director, Discovery & Research of Ono. "Through this drug discovery collaboration, we are excited to work with PRISM to identify and develop novel small molecule drugs for therapeutic targets that had been previously difficult to modulate with a small molecule, leading to further expansion of our development pipeline to address unmet medical needs across a broad range of diseases." "We are very excited to enter into this collaboration with Ono who has a history of creating innovative drugs. ", said Dai Takehara, President & CEO of PRISM Biolab. "We believe that our PepMetics® technology will change the current paradigm in drug discovery by turning previously undruggable PPIs into targets readily druggable with small molecules. Through close collaboration between creative scientists of both companies, we expect to generate innovative and game-changing drugs for the benefit of patients." About Ono Pharmaceutical Co., Ltd. Ono Pharmaceutical Co., Ltd., headquartered in Osaka, is an R&D-oriented pharmaceutical company committed to creating innovative medicines in specific areas. ONO focuses its research on the oncology, immunology, neurology and specialty research with high medical needs as priority areas for discovery and development of innovative medicines. For further information, please visit the company's website at . About PRISM BioLab PRISM BioLab is a discovery and development biotechnology company utilizing proprietary PepMetics® technology to discover orally available small molecule inhibitors of protein-protein interaction (PPI) targets and transform lives of patients suffering from cancer, autoimmune, fibrosis and other diseases. PepMetics® are a unique class of small molecules that mimic three-dimensional structures of alpha-helix and beta-turn, the peptide structures commonly found in intracellular PPI interphases and receptor-ligand interactions. By combining proprietary chemistry, know-how around PPI targets and AI-supported design, PepMetics® technology can deliver inhibitors of challenging PPI targets. The technology holds promise to expand the field of drug discovery by turning previously undruggable PPIs into targets readily druggable with small molecules and by generating oral small molecule alternatives for injectable biologics. PRISM BioLab is collaborating on new PPI targets with global and Japanese pharmaceutical companies. PepMetics® targeting CBP/beta-catenin PPIs licensed to Eisai Co., Ltd. and Ohara Pharmaceuticals Co., Ltd. are in clinical development for cancer and liver disease, respectively. SOURCE PRISM BioLab Co., Ltd.

引进/卖出

2024-01-24

·PRNewswire

PRISM BioLab raises 1.5 billion yen in Series C fundraising to advance technologies and programs targeting protein-protein interactions

Eli Lilly and Company, Santec Holdings Corporation participated in the round TOKYO, Jan. 24, 2024 /PRNewswire/ -- TOKYO, Jan. 24, 2024 /PRNewswire/ -- PRISM BioLab, Co. Ltd. ("PRISM"), a leading discovery and development biotechnology company designing small molecule inhibitors of protein-protein interaction (PPI) targets, today announced a 1.5 billion yen ($10.3M) fundraise. Funds will be used to refine PRISM's proprietary PepMetics® chemistry platform, expand biology and screening capabilities and advance internal pipeline of PPI inhibitors. As the numbers of so called "druggable" targets are dwindling, pharma is gradually turning to PPI targets. Due to frequent involvement in the disease and a sheer number of PPIs, they have long been recognized as a new frontier for drug discovery but the progress has been hampered by the lack of chemistries that can successfully address PPI targets. PRISM BioLab has early recognized the importance of PPIs as drug targets and has spent over a decade developing proprietary PepMetics® chemical scaffolds that mimic three-dimensional structure of the alpha-helix and beta-turn, peptide structures commonly found in PPI interphases. Today, PepMetics® chemistry enables systematic and reproducible discovery and development of drugs targeting PPIs. "We are confident that our PepMetics® chemistry will become one of the key technologies for the PPI target field," said Dai Takehara, CEO of PRISM BioLab. "The funds from this financing round will be used to integrate our PepMetics® chemistry, biology and screening capabilities, to advance our internal pipeline, and to provide greater value to our existing and future pharma partners. We recognize the importance of partnerships for the success of new approaches to drug discovery and are fortunate to build a long-term relationship with Lilly, a top pharma company, as we move the field forward." Comments from investors Santec Holdings Corporation Executive Vice President & CTO Changho Chong Ph.D. We feel confident that PRISM BioLab's promising and unique approach to drug discovery will lead to breakthrough therapeutic drugs that were previously unattainable. Santec is engaged in the development of medical imaging devices and early diagnosis utilizing Photonics. We believe that the advancement of these technologies, in conjunction with innovative drug discovery techniques, is pivotal for the comprehensive improvement of patients' Quality of Life (QoL). About PRISM BioLab PRISM BioLab is a discovery and development biotechnology company utilizing proprietary PepMetics® technology to discover orally available small molecule inhibitors of protein-protein interaction (PPI) targets and transform lives of patients suffering from cancer, autoimmune, fibrosis and other diseases. PepMetics® are a unique class of small molecules that mimic three-dimensional structures of alpha-helix and beta-turn, the peptide structures commonly found in intracellular PPI interphases and receptor-ligand interactions. By combining proprietary chemistry, know-how around PPI targets and AI-supported design, PepMetics® technology can deliver inhibitors of challenging PPI targets. The technology holds promise to expand the field of drug discovery by turning previously undruggable PPIs into targets readily druggable with small molecules and by generating oral small molecule alternatives for injectable biologics. PRISM BioLab is collaborating on new PPI targets with global and Japanese pharmaceutical companies. PepMetics® targeting CBP/beta-catenin PPIs licensed to Eisai Co., Ltd. and Ohara Pharmaceuticals Co., Ltd. are in clinical development for cancer and liver disease, respectively. SOURCE PRISM BioLab Co., Ltd.

100 项与 Proteogenomics Research Institute for Systems Medicine 相关的药物交易

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100 项与 Proteogenomics Research Institute for Systems Medicine 相关的转化医学

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