Development of a Designer Proline-rich antimicrobial peptide Chaperone protein inhibitor (DPC) for treating sepsis

开发用于治疗脓毒症的富含脯氨酸的抗菌肽伴侣蛋白抑制剂 (DPC)

基本信息

批准号：
10007300
负责人：
Carl Neil Kraus
金额：
$ 30万
依托单位：
ARREVUS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-21 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10007300
关键词：
Address Adjuvant Therapy Adrenal Cortex Hormones Agonist Animals Antibiotic Resistance Antibiotic Therapy Antibiotics Azithromycin Bacterial Infections Bacterial Model Bacterial Proteins Binding CD28 gene CD3 Antigens Catabolism Cessation of life Chronic Chronic stress Colistin Critical Illness Data Development Disease Dysplasia Elderly Evaluation Exhibits Experimental Models Functional disorder Goals Guidelines Heat shock proteins Homologous Gene Hospitals Human Imipenem Immune Immune response Immunity Immunologics Immunosuppression Individual Infection Inflammation Inflammatory Inflammatory Response Insecta Interferons Lead Life Liquid substance Measurement Measures Mechanical ventilation Medical Membrane Lipids Modeling Molecular Chaperones Multi-Drug Resistance Multiple Bacterial Drug Resistance Mus Natural Immunity Patients Peripheral Peripheral Blood Mononuclear Cell Peritonitis Pharmaceutical Preparations Phase Plasma Populations at Risk Positioning Attribute Production Program Development Proline Property Proteins Recovery Resuscitation Safety Sepsis Small Business Technology Transfer Research Splenocyte Stress Supportive care Survivors Syndrome T-Lymphocyte TNF gene Therapeutic Therapeutic Intervention Treatment Efficacy Treatment Failure Whole Blood adaptive immune response adaptive immunity antimicrobial antimicrobial drug antimicrobial peptide bacterial resistance blood product cecal ligation puncture cytokine drug resistant pathogen effective therapy immunoregulation immunosuppressed improved in vivo inhibitor/antagonist monocyte mortality mouse model multi-drug resistant pathogen novel novel strategies novel therapeutics organ injury pathogenic bacteria peripheral blood phase 2 study polymicrobial sepsis pre-clinical programs protein folding response septic patients systemic inflammatory response treatment risk treatment strategy

项目摘要

PROJECT SUMMARY Sepsis is a life-threatening syndrome that involves a systemic inflammatory response that is initiated by an infection. There are an estimated 1.5 million of cases annually in the US with 250,000 resulting in death. The number of cases and associated deaths is expected to increase given the rising at-risk population of elderly individuals and the compounding challenge of antibiotic resistance. Treatment of sepsis involves antimicrobial therapy in addition to several supportive care measures to address the complications of the systemic inflammatory response. In order to effectively and appropriately address the pathophysiological aspects of sepsis, a treatment must provide antimicrobial activity in addition to immunomodulatory properties. It is imperative that efforts to identify new and effective treatment strategies for sepsis shift from the traditional antibiotic development programs that focus solely on antimicrobial activity and turn toward strategies that address both antimicrobial and immunomodulatory aspects of the disease. Arrevus is developing a novel approach to addressing sepsis using Designer Proline-rich Antimicrobial peptide Chaperone protein inhibitors (DPCs), derived from insects and selectively modified, acting as inhibitors to one of the critical bacterial proteins responsible for bacterial protein folding, DnaK. As an adjuvant therapy to current antibiotics, DPCs have the potential to provide a much-improved treatment option for multi-drug resistant (MDR) bacterial infections. Preliminary studies have displayed the potential of ARV-1502, the lead DPC, as an effective antimicrobial agent against MDR bacterial pathogens in addition to providing immunomodulatory effects. Specifically, our efforts have shown that: 1) DPCs show efficacy against MDR pathogens (both gram-negative and gram-positive) alone and in combination with traditional antibiotics; 2) DPCs offer a novel and specific bacterial target; 3) ARV-1502 has demonstrated immunomodulatory properties; and 4) ARV-1502 exhibits a favorable safety profile. Collectively, these data support the continued development of ARV-1502 through an STTR Phase I program targeting proof-of-concept data for the use of ARV-1502 in the treatment of sepsis. In this Phase I proposal, we will build upon significant preliminary data to demonstrate proof-of-concept for the use of ARV-1502 for treating sepsis through two aims. In Aim 1, we will characterize the effect of ARV- 1502 treatment on host innate and adaptive immunity using peripheral blood monocytes and T-cells from sepsis patients. In Aim 2, we will assess the in vivo efficacy of ARV-1502 in murine sepsis models to improve survival (in aim 2A using a near-lethal sepsis model) and host protective immunity (in aim 2B using a survivable murine sepsis model in which animals survive the initial infection but are immunosuppressed). The overall goal of this Phase I program is to generate initial proof-of-concept data and to assess when and how ARV-1502 would be best utilized in sepsis.

项目概要脓毒症是一种危及生命的综合征，涉及由脓毒症引发的全身炎症反应。感染。据估计，美国每年有 150 万例病例，其中 25 万人死亡。这鉴于老年人高危人口不断增加，预计病例数和相关死亡人数将会增加个体和抗生素耐药性的复杂挑战。脓毒症的治疗涉及抗菌药物除了一些支持性护理措施之外，还需要进行治疗以解决系统性并发症炎症反应。为了有效和适当地解决病理生理学方面对于脓毒症，除了免疫调节特性之外，治疗还必须提供抗菌活性。这是当务之急是寻找新的、有效的脓毒症治疗策略，从传统的治疗策略转向抗生素开发计划仅关注抗菌活性并转向以下战略：解决该疾病的抗菌和免疫调节方面的问题。 Arrevus 正在开发一种使用富含脯氨酸的设计师抗菌剂来解决败血症的新方法肽伴侣蛋白抑制剂 (DPC)，源自昆虫并经过选择性修饰，充当抑制剂负责细菌蛋白质折叠的关键细菌蛋白质之一 DnaK。作为辅助治疗与目前的抗生素相比，DPC 有潜力为多种药物提供大大改善的治疗选择耐药（MDR）细菌感染。初步研究显示了 ARV-1502 的潜力 DPC 作为一种有效的抗 MDR 细菌病原体的抗菌剂，除了提供免疫调节作用。具体来说，我们的努力表明：1) DPC 显示出对抗 MDR 的功效单独或与传统抗生素联合使用病原体（革兰氏阴性和革兰氏阳性）； 2） DPC 提供了一种新颖且特定的细菌靶标； 3) ARV-1502已被证明具有免疫调节作用特性; 4) ARV-1502 表现出良好的安全性。总的来说，这些数据支持持续通过 STTR 第一阶段计划开发 ARV-1502，目标是使用概念验证数据 ARV-1502 治疗脓毒症。在第一阶段提案中，我们将基于重要的初步数据来证明概念验证使用 ARV-1502 治疗脓毒症有两个目的。在目标 1 中，我们将描述 ARV 的作用- 1502 使用外周血单核细胞和 T 细胞对宿主先天性和适应性免疫进行治疗败血症患者。在目标 2 中，我们将评估 ARV-1502 在小鼠脓毒症模型中的体内功效，以改善生存（在目标 2A 中使用近乎致命的脓毒症模型）和宿主保护性免疫（在目标 2B 中使用可存活的鼠败血症模型，其中动物在最初的感染中存活下来，但免疫抑制）。这该第一阶段计划的总体目标是生成初始概念验证数据并评估何时以及如何 ARV-1502 最适合用于治疗脓毒症。