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

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.

用于治疗脓毒症的新型肽免疫调节剂脓毒症是一种危及生命的临床疾病，由宿主免疫失调引起对感染的反应，导致约 170 万美国成年人出现多器官衰竭。每年导致 27 万人住院，其中近 50% 的幸存者死亡。脓毒症患者重新住院，六分之一的幸存者无法存活超过一年。其特点是菌血症增加，导致超系统性炎症反应免疫稳态无法正常化导致感染性休克5。然而，目前还没有针对细菌感染的抗生素和针对目标器官的支持治疗。目前可用于靶向治疗超免疫反应的药物，表明存在 Orai1 是质膜 Ca2+ 通道，是进行性脓毒症治疗中未满足的关键需求。调节钙离子进入 (SOCE)，这是一个基本过程。参与炎症信号转导并调节 NF-κB 介导的转录和分泌短腭肺和鼻上皮克隆 1 (SPLUNC1) 是一种炎症反应。我们发现SPLUNC1的C端α6区域是一个特定的分泌型先天防御蛋白。 Orai1 的抑制剂因此，SPLUNC1/α6 负向调节 Orai1 以减少 SOCE 和因此，Eldec 计划使用 α6 肽模拟物来抑制 Orai1。 Eldec 成功开发了 SPLUNC1 ELD607。完全尺寸优化的肽模拟物，并且显着更有效且更具蛋白水解性我们发现 ELD607 显着降低 Orai1/SOCE 和随后与败血症和/或细菌性肺炎相关的炎症反应。初步数据表明，ELD607 可减少金黄色葡萄球菌和假单胞菌引起的败血症。此外，用 ELD607 治疗的小鼠中，铜绿假单胞菌的数量有所增加。生存率，表明 ELD607 不具有免疫抑制作用。在 LPS 诱导的脓毒症模型中，血液中性粒细胞减少并改善体重。研究表明 ELD607 是一种新型免疫调节剂，可有效对抗脓毒症。我们承认小鼠脓毒症模型的局限性，因此，为了更好地转化我们的发现，我们将评估 ELD607 作为人类脓毒症患者免疫中脂多糖诱导的脓毒症的治疗方法我们将首先评估 ELD607 人血清的稳定性。然后我们将评估 ELD607 对脓毒症患者血液中性粒细胞的功效。然后，我们将验证 ELD607 在非人灵长类动物中对 LPS 诱导的败血症的疗效。为了研究 ELD607 对减少败血症疾病进展的影响。