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:
- 金额:$ 30万
- 依托单位:
- 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:
- 关键词:AddressAdjuvant TherapyAdrenal Cortex HormonesAgonistAnimalsAntibiotic ResistanceAntibiotic TherapyAntibioticsAzithromycinBacterial InfectionsBacterial ModelBacterial ProteinsBindingCD28 geneCD3 AntigensCatabolismCessation of lifeChronicChronic stressColistinCritical IllnessDataDevelopmentDiseaseDysplasiaElderlyEvaluationExhibitsExperimental ModelsFunctional disorderGoalsGuidelinesHeat shock proteinsHomologous GeneHospitalsHumanImipenemImmuneImmune responseImmunityImmunologicsImmunosuppressionIndividualInfectionInflammationInflammatoryInflammatory ResponseInsectaInterferonsLeadLifeLiquid substanceMeasurementMeasuresMechanical ventilationMedicalMembrane LipidsModelingMolecular ChaperonesMulti-Drug ResistanceMultiple Bacterial Drug ResistanceMusNatural ImmunityPatientsPeripheralPeripheral Blood Mononuclear CellPeritonitisPharmaceutical PreparationsPhasePlasmaPopulations at RiskPositioning AttributeProductionProgram DevelopmentProlinePropertyProteinsRecoveryResuscitationSafetySepsisSmall Business Technology Transfer ResearchSplenocyteStressSupportive careSurvivorsSyndromeT-LymphocyteTNF geneTherapeuticTherapeutic InterventionTreatment EfficacyTreatment FailureWhole Bloodadaptive immune responseadaptive immunityantimicrobialantimicrobial drugantimicrobial peptidebacterial resistanceblood productcecal ligation puncturecytokinedrug resistant pathogeneffective therapyimmunoregulationimmunosuppressedimprovedin vivoinhibitor/antagonistmonocytemortalitymouse modelmulti-drug resistant pathogennovelnovel strategiesnovel therapeuticsorgan injurypathogenic bacteriaperipheral bloodphase 2 studypolymicrobial sepsispre-clinicalprogramsprotein foldingresponseseptic patientssystemic inflammatory responsetreatment risktreatment 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.
项目摘要
脓毒症是一种危及生命的综合征,其涉及全身性炎症反应,
感染据估计,美国每年有150万例病例,其中25万例导致死亡。的
由于老年高危人群不断增加,
个体和抗生素耐药性的复合挑战。脓毒症的治疗涉及抗菌药物
除了几种支持性护理措施外,还可以进行治疗,以解决全身性并发症。
炎症反应。为了有效和适当地解决的病理生理方面的
对于脓毒症,治疗必须提供除免疫调节性质之外的抗微生物活性。是
当务之急是努力确定新的和有效的治疗策略,脓毒症从传统的
抗生素开发计划只关注抗菌活性,并转向
解决疾病的抗微生物和免疫调节方面。
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),来源于昆虫并选择性修饰,用作抑制剂
一种负责细菌蛋白质折叠的关键细菌蛋白质,DnaK。作为辅助疗法用于
目前的抗生素,DPC有可能为多药治疗提供一个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,我们的努力已经表明:1)DPC对MDR显示出功效
病原体(革兰氏阴性和革兰氏阳性)单独和与传统抗生素组合; 2)
DPC提供了一种新的和特异性的细菌靶点; 3)ARV-1502已证明具有免疫调节作用
4)ARV-1502表现出良好的安全性。总的来说,这些数据支持持续的
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治疗败血症
在第一阶段提案中,我们将基于重要的初步数据来证明以下内容的概念验证
ARV-1502通过两个目的用于治疗脓毒症的用途。在目标1中,我们将描述抗逆转录病毒药物的作用-
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的治疗
败血症患者在目标2中,我们将评估ARV-1502在鼠脓毒症模型中的体内功效,以改善ARV-1502的体内毒性。
存活(在目的2A中,使用近致死性脓毒症模型)和宿主保护性免疫(在目的2B中,使用
可存活的鼠脓毒症模型,其中动物在初始感染中存活但免疫抑制)。的
第一阶段计划的总体目标是生成初步的概念验证数据,并评估何时以及如何进行
ARV-1502最好用于脓毒症。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Carl Neil Kraus其他文献
Carl Neil Kraus的其他文献
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10599656 - 财政年份:2023
- 资助金额:
$ 30万 - 项目类别:
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