Novel Peptide Immunomodulators for Treating Sepsis

用于治疗脓毒症的新型肽免疫调节剂

基本信息

批准号：
10602761
负责人：
Saira Ahmad
金额：
$ 25.91万
依托单位：
ELDEC PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-03 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10602761
关键词：
Adult Animals Antibiotics Antisepsis Bacteremia Bacterial Infections Bacterial Pneumonia Biological Availability Biological Markers Biology Blood C-terminal Capital Cell membrane Cells Cessation of life Clinical Clinical Trials Data Development Disease Progression Doctor of Philosophy Equilibrium Escherichia coli Etiology Failure Formulation Foundations Genetic Transcription Glosso-Sterandryl Homeostasis Hospitalization Human Immune Immune response Immunomodulators Infection Inflammation Inflammatory Inflammatory Response Intravenous Knock-out Lead Leukocyte Elastase Life Lung Mediating Modeling Multiple Organ Failure Mus Nasal Epithelium Neutrophilia Organ Palate Peptides Personal Satisfaction Pharmaceutical Preparations Phase Pre-Clinical Model Privatization Process Proteins Pseudomonas aeruginosa Public Health Research Safety Sepsis Septic Shock Septicemia Serum Services Signal Transduction Staphylococcus aureus Supportive care Survivors Testing Therapeutic Translating Treatment Efficacy Universities Weight Work clinical development forest hospital readmission improved inhibitor intravenous administration intravenous injection lead candidate mouse model neutrophil nonhuman primate novel novel strategies peptidomimetics pneumonia model pre-clinical prevent programs septic patients systemic inflammatory response vervet

Adult Animals Antibiotics Antisepsis Bacteremia Bacterial Infections Bacterial Pneumonia Biological Availability Biological Markers Biology Blood C-terminal Capital Cell membrane Cells Cessation of life Clinical Clinical Trials Data Development Disease Progression Doctor of Philosophy Equilibrium Escherichia coli Etiology Failure Formulation Foundations Genetic Transcription Glosso-Sterandryl Homeostasis Hospitalization Human Immune Immune response Immunomodulators Infection Inflammation Inflammatory Inflammatory Response Intravenous Knock-out Lead Leukocyte Elastase Life Lung Mediating Modeling Multiple Organ Failure Mus Nasal Epithelium Neutrophilia Organ Palate Peptides Personal Satisfaction Pharmaceutical Preparations Phase Pre-Clinical Model Privatization Process Proteins Pseudomonas aeruginosa Public Health Research Safety Sepsis Septic Shock Septicemia Serum Services Signal Transduction Staphylococcus aureus Supportive care Survivors Testing Therapeutic Translating Treatment Efficacy Universities Weight Work clinical development forest hospital readmission improved inhibitor intravenous administration intravenous injection lead candidate mouse model neutrophil nonhuman primate novel novel strategies peptidomimetics pneumonia model pre-clinical prevent programs septic patients systemic inflammatory response vervet

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项目摘要

Novel Peptide Immunomodulators for Treating Sepsis Sepsis is a life-threatening clinical condition which results from a dysregulation of host immune responses to infection, which leads to multi-organ failure. Sepsis occurs in ~1.7 million US adults annually resulting in hospitalization and 270,000 deaths. Of those that survive, nearly 50% of sepsis patients are re-hospitalized and one in six of survivors do not survive past one year. Sepsis is characterized by increased bacteremia resulting in hyper-systemic inflammatory responses and a failure to normalize immune homeostasis resulting in septic shock5. Treatment consists of antibiotics to target bacterial infections and supportive care for targeted organs. However, no drugs are currently available to target and treat the hyper immune response, indicating that there is critical unmet need for progressive sepsis therapies. Orai1 is a plasma membrane Ca2+ channel that regulates store operated Ca2+ entry (SOCE), a fundamental process. Orai1/SOCE is proximal in inflammatory signaling and regulates NF-κB-mediated transcription and secretion of pro- inflammatory responses. Short Palate LUng and Nasal epithelial Clone 1 (SPLUNC1) is a secreted innate defense protein. We found that SPLUNC1’s C-terminal α6 region is a specific inhibitor of Orai1. Thus, SPLUNC1/α6 negatively regulates Orai1 to reduce SOCE and inflammation. Eldec therefore plans to inhibit Orai1 using α6 peptidomimetics to inhibit inflammation during sepsis. Eldec has successfully developed ELD607, a SPLUNC1 peptidomimetic that is fully size- optimized, and significantly more potent and more proteolytically stable than SPLUNC1 α6. We have found that ELD607 significantly reduces Orai1/SOCE and subsequent inflammatory responses associated with sepsis and/or bacterial pneumonia. Our preliminary data demonstrate that ELD607 reduces sepsis caused by S. aureus and P. aeruginosa in murine pneumonia models. Additionally, mice treated with ELD607 had increased survival, suggesting that ELD607 is not immunosuppressive. Our data also indicate that ELD607 reduced blood neutrophilia and improved weight in an LPS-induced sepsis model. Thus, our studies demonstrate that ELD607 is a novel immunomodulator that is effective against sepsis. We acknowledge the limitations of murine sepsis models. Thus, to better translate our findings, we will evaluate ELD607 as a treatment for LPS-induced sepsis in human sepsis patient immune cells and in nonhuman primates. We will first evaluate the stability of ELD607 human serum from sepsis patients. We will then evaluate ELD607’s efficacy in human blood neutrophils of sepsis patients. We will then validate ELD607’s efficacy in nonhuman primates in an LPS-induced sepsis in order to study the impact of ELD607 on reducing sepsis disease progress.

用于治疗败血症的新型肽免疫调节剂败血症是一种威胁生命对感染的反应，导致多器官失败。败血症发生在约170万美国成年人中一点点导致住院和270,000人死亡。在生存的人中，几乎50％败血症患者被重新住院，六分之一的存活率在过去一年中无法生存。败血症其特征是细菌增加，导致超系统炎症反应和未能使免疫稳态归一化导致败血性休克5。治疗包括抗生素靶向细菌感染和针对性器官的支持性护理。但是，不目前可用于靶向和治疗超免疫反应，表明那里是对进行性败血症疗法的关键需求。 Orai1是质膜Ca2+通道调节商店经营的CA2+输入（SOCE），这是一个基本过程。 ORAI1/SOCE近端在炎症信号传导中，调节NF-κB介导的转录和分泌炎症反应。短口肺和鼻上皮克隆1（Splunc1）是一个分泌的先天防御蛋白。我们发现Splunc1的C末端α6区域是特定的 Orai1的抑制剂。这就是slpunc1/α6负调节Orai1以减少SOCE和炎。因此，ELDEC计划使用α6Pepperomipimetics抑制ORAI1抑制败血症期间的炎症。 ELDEC已成功开发了ELD607，Splunc1 完全优化的肽瘤稳定比Splunc1α6。我们发现ELD607大大降低了Orai1/Soce和随后与败血症和/或细菌性肺炎有关的炎症反应。我们的初步数据表明，ELD607降低了由金黄色葡萄球菌和P引起的败血症。鼠类肺炎模型中的铜绿物。此外，用ELD607处理的小鼠增加了生存，表明ELD607不是免疫抑制。我们的数据还表明ELD607 在LPS诱导的败血症模型中，血液中性粒细胞减少并改善了体重。那，我们的研究表明，ELD607是一种有效抗败血症的新型免疫调节剂。我们承认鼠类败血症模型的局限性。为了更好地翻译我们的发现，我们将评估ELD607作为LPS诱导的人类败血症患者免疫的治疗方法细胞和非人类隐私。我们将首先评估ELD607人血清的稳定性败血症患者。然后，我们将评估ELD607在败血症的人类血液中性粒细胞中的效率患者。然后，我们将验证ELD607在LPS引起的败血症中的非人类灵长类动物的效率为了研究ELD607对减少败血症进展的影响。