ELD607 Orai1 Antagonist Increases Bacterial Clearance from the Lung

ELD607 Orai1 拮抗剂可增加肺部细菌清除率

• 批准号: 10453601
• 负责人: ROBERT TARRAN
• 金额: $ 98.82万
• 依托单位: ELDEC PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-22 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10453601
• 关键词: Address; Affect; Animals; Antibiotic Resistance; Antibiotics; Bacteremia; Bacteria; Bacterial Antibiotic Resistance; Bacterial Infections; Binding; Biological Assay; Biotechnology; Bronchoalveolar Lavage; Cell Line; Cell membrane; Cells; Clinical Data; Contracts; Critical Illness; Data; Development; Diagnosis; Dose; Drug Kinetics; ESKAPE pathogens; Early treatment; Effectiveness; Frequencies; Glosso-Sterandryl; Immune; Immune system; Immunofluorescence Immunologic; Infection; Inflammation; Inflammatory Response; Inhalation; Intensive Care Units; Ion Channel; Klebsiella pneumoniae; Lead; Leukocyte Elastase; Lung; Macaca mulatta; Modeling; Mus; Nasal Epithelium; Neutrophilia; Nosocomial Infections; Nosocomial pneumonia; Organism; Outcome; Palate; Patients; Peptides; Pharmacologic Substance; Pharmacology and Toxicology; Phase; Play; Pneumonia; Population; Production; Proteins; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Public Health; Regimen; Resistance; Role; Sepsis; Signal Transduction; Specificity; Staphylococcus aureus; Testing; Therapeutic; Toxicology; Tropism; Validation; Western Blotting; antagonist; base; clinical development; effective therapy; experimental study; improved; improved outcome; lung health; lung injury; meetings; methicillin resistant Staphylococcus aureus; mortality; mouse model; neutrophil; novel; novel strategies; novel therapeutic intervention; pathogen; patient population; peptidomimetics; pneumonia model; polypeptide; pre-clinical; programs; public health relevance; reconstitution; resistant strain; validation studies

Abstract Hospital acquired pneumonia (HAP) is most common cause of mortality in intensive care units and the 2nd most common nosocomial infection in the US. P. aeruginosa, S. aureus (including MRSA) and other ESKAPE pathogens are common causes of HAP. The rise in antibiotic-resistant bacteria, including MRSA, further complicates the challenges of delivering effective treatments in this patient population. New approaches beyond traditional antibiotics are urgently need to improve outcomes in HAP patients. The innate immune protein Short Palate LUng and Nasal epithelial Clone 1 (SPLUNC1) is secreted into the lung lumen, where it can bind to and regulate ion channels. Orai1 is a ubiquitously-expressed plasma membrane Ca2+ channel, whose activation is required for the onset of inflammation. We have identified SPLUNC1’s Orai1-inhibitory domain, termed the a6 region: SPLUNC1 and a6 negatively regulate Orai1 to moderate Ca2+ signaling and reduce inflammation. However, both SPLUNC1 and the a6 peptide are rapidly degraded by neutrophil elastase, limiting their effectiveness in reducing Ca2+ signaling and inflammation in pneumonia, which is characterized by neutrophilia. Eldec Pharma has developed a robust, novel peptidomimetic called ELD607, which reconstitutes SPLUNC1/a6’s ability to inhibit Orai1, yet is significantly more resistant to degradation by neutrophil elastase than a6. In murine pneumonia models with P. aeruginosa and S. aureus, a single, inhaled dose of ELD607 reduced lung neutrophilia by 90%, decreased lung bacterial infection by 3-5 log10 CFUs, reduced sepsis, and increased survival. These definitive experiments demonstrate that rebalancing the lung’s inflammatory response via ELD607 enhances the lungs’ natural ability to clear pathogens, in the absence of antibiotics. This capacity is predicted to make concurrently-administered antibiotics more effective, providing an important new therapeutic strategy to help address the emergence of antibiotic-resistant strains of bacteria. The ability of ELD607 to inhibit Orai1 and increase bacterial clearance represents a revolutionary approach to improving HAP outcomes. Robust validation of ELD607 in Phase I will enable Eldec Pharma to request a pre-IND meeting with the FDA, in order to perform IND-enabling studies in Phase II and to make the subsequent transition to clinical development. Phase 1 Aim 1. To confirm that ELD607 replicates the Orai1-tropism observed with SPLUNC1/a6. Aim 2. To replicate ELD607’s ability to clear other ESKAPE pathogens. Phase 2 Aim 3 To produce GLP grade ELD607 to support downstream development activities. Aim 4. To determine the optimal dosing regimen of ELD607 in a murine model. Aim 5. To validate the ELD607 dosing regimen in a Rhesus macaque model of HAP.

抽象的 医院获得性肺炎 (HAP) 是重症监护室最常见的死亡原因，而铜绿假单胞菌、金黄色葡萄球菌（包括 MRSA）和其他 ESKAPE 病原体是 HAP 上升的常见原因。包括 MRSA 在内的抗生素耐药性细菌的存在，使得在该患者群体中提供有效治疗的挑战进一步复杂化，迫切需要超越传统抗生素的新方法来改善 HAP 患者的治疗结果。蛋白质短腭 LUng 和鼻上皮克隆 1 (SPLUNC1) 分泌到肺腔中，它可以结合并调节离子通道 Orai1 是一种普遍表达的质膜 Ca2+ 通道，其激活是炎症发生所必需的。我们已经确定了 SPLUNC1 的 Orai1 抑制域，称为 a6 区域：SPLUNC1 和 a6 负向调节 Orai1 以调节 Ca2+然而，SPLUNC1 和 a6 肽都会被中性粒细胞弹性蛋白酶快速降解，从而限制了它们在以中性粒细胞增多为特征的肺炎中减少 Ca2+ 信号传导和炎症的有效性，Eldec Pharma 开发了一种名为 ELD607 的强大新型肽模拟物。它重建了 SPLUNC1/a6 抑制 Orai1 的能力，但比 a6 In 更能抵抗中性粒细胞弹性蛋白酶的降解。使用铜绿假单胞菌和金黄色葡萄球菌的小鼠肺炎模型，单次吸入剂量的 ELD607 可使肺部中性粒细胞减少 90%，使肺部细菌感染减少 3-5 log10 CFU，减少脓毒症，并提高生存率。在没有抗生素的情况下，肺部通过 ELD607 产生的炎症反应增强了肺部清除病原体的自然能力。 ELD607 抑制 Orai1 和增加细菌清除的能力代表了改善 HAP 结果的革命性方法。第一阶段的进展将使 Eldec Pharma 能够请求与 FDA 召开 IND 前会议，以便在第二阶段进行 IND 支持研究，并随后过渡到临床开发目标 1。确认 ELD607 复制了 SPLUNC1/a6 观察到的 Orai1 向性。 目标 2。复制 ELD607 清除其他 ESKAPE 病原体的能力。 目标 3 生产 GLP 级 ELD607 以支持下游开发活动。目的 5. 在小鼠模型中验证 ELD607 的给药方案。 HAP 恒河猴模型。

项目成果

Specific Inhibition of Orai1-mediated Calcium Signalling Resolves Inflammation and Clears Bacteria in an Acute Respiratory Distress Syndrome Model.

特异性抑制 Orai1 介导的钙信号传导可解决急性呼吸窘迫综合征模型中的炎症并清除细菌。

• 发表时间: 2024-03-15
• 影响因子: 24.7
• 作者: Ahmad, Saira;Wrennall, Joe A;Goriounova, Alexandra S;Sekhri, Malika;Iskarpatyoti, Jason A;Ghosh, Arunava;Abdelwahab, Sabri H;Voeller, Alexis;Rai, Mani;Mahida, Rahul Y;Krajewski, Krzysztof;Ignar, Diane M;Greenbaum, Alon;Moran, Timothy P;Tille
• 通讯作者: Tille