Validation and early development of a blood-based rapid diagnostic test for sepsis endotypes

脓毒症内型基于血液的快速诊断测试的验证和早期开发

• 批准号: 10324978
• 负责人: Timothy E Sweeney
• 金额: $ 68.39万
• 依托单位: INFLAMMATIX, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10324978
• 关键词: Acute; Affect; Antibiotics; Biological; Biological Assay; Blood; Blood Tests; Cell Line; Cessation of life; Characteristics; Classification; Clinic; Clinical; Clinical Research; Clinical Trials; Cohort Analysis; Communicable Diseases; Complication; Custom; Data; Data Set; Development; Devices; Diagnosis; Diagnostic tests; Disease; Drug Targeting; Face; Failure; Functional disorder; Future; Gene Expression Profile; Genes; Goals; Heterogeneity; Immune; Immune response; Infection; Inflammatory; Inflammatory Response; Intervention; Intervention Trial; Libraries; Life; Link; Machine Learning; Measures; Messenger RNA; Methods; Modeling; Molecular; Network-based; Oncology; Organ; Outcome; Paper; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase I/II Clinical Trial; Phenotype; Process; Prognostic Marker; Prospective Studies; Prospective cohort; Public Health; Publications; Rapid diagnostics; Reproducibility; Research; Resource Allocation; Retrospective cohort; Safety; Sampling; Selection for Treatments; Sepsis; Series; Severities; Subgroup; Supportive care; System; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Training; Translating; Translations; Treatment Protocols; United States National Institutes of Health; Update; Validation; Venipunctures; Work; base; biomarker signature; clinically actionable; cohort; companion diagnostics; design; diagnostic biomarker; drug action; drug candidate; drug repurposing; fighting; genetic signature; immunoregulation; improved; innovation; learning classifier; machine learning algorithm; mortality; novel; novel diagnostics; novel strategies; pathogen; patient stratification; point of care; point of care testing; precision medicine; product development; rapid test; response; septic patients; success; tool; transcriptomics

ABSTRACT Sepsis, a systemic inflammatory condition, occurs as a complication of infection and in severe cases may be associated with acute and life-threatening organ dysfunction. In the US alone, sepsis claims ~270,000 lives each year among ~1.7 million patients diagnosed annually, and globally, sepsis-related mortality is estimated to account for 20% of total deaths. Although improvements in the treatment protocol for sepsis and timely administration of antibiotics have reduced mortality rates, not a single drug for sepsis has ever been successfully brought to market, despite over 100 interventional trials, and it is treated today as 60 years ago: antibiotics and supportive care. Sepsis is unusual in that a great deal of the immune response is actually adaptive (beneficial) vs. disease-causing (maladaptive), so reversing the inflammatory response can cause the infection to go unchecked. We believe that a treatment should reverse the maladaptive (organ-damaging) components of the immune response, while keeping the adaptive (pathogen-fighting) components intact. We believe that to achieve impactful progress, new approaches are required that harness immune sub-groups. In this project, we propose a precision medicine approach to subdivide sepsis patients into treatable subclasses or “endotypes” using a companion diagnostic test, HostDx-Endotypes. We anticipate that classifying sepsis patients into such endotypes may allow us to identify improved treatment regimens, leading to the discovery of new targets or pathways for endotype-specific therapies and/or repurposing of available drugs. In Phase 1 work we already demonstrated proof-of-concept by identifying 3 sepsis endotypes (Inflammopathic, Adaptive, and Coagulopathic) and validated across multiple external data sets. We have shown that our HostDx Endotypes can stratify patients into novel, potentially treatable subgroups across 3 publications using several retrospective cohorts, and two prospective cohorts. We have also demonstrated the clinical utility of this paradigm with InSepTM, our robust classifier for acute infectious disease, based on our HostDx point of care test system platform. To bridge our proof-of-concept work to product development for HostDx-Endotypes, we will (Aim 1) employ rigorous machine learning algorithms and processes to finalize and lock an optimal classifier; (Aim 2) apply an innovative approach of drug repurposing to identify and rank-order endotype-specific drug candidates for clinical studies on sepsis treatment, and (Aim 3) translate the final mRNA panel to Inflammatix’s qLAMP cartridge and platform. At Phase II completion we will have produced the HostDx Endotypes research-ready cartridge, together with a list of repurposed drugs for intended clinical trials, and will be ready to enter the formal product development phase; we will have initiated the FDA pre-submission. Ultimately, the goal of this product will be to definitively link a patient sepsis endotype with a therapeutic intervention, to enable better therapy selection and resource allocation.

抽象的 脓毒症是一种全身性炎症，是感染的并发症，在严重的情况下可能会 与急性和危及生命的器官功能障碍有关。仅在美国，脓毒症就夺去了约 27 万人的生命 每年诊断出约 170 万名患者，在全球范围内，脓毒症相关死亡率估计 占总死亡人数的20%。尽管败血症治疗方案的改进和及时 抗生素的使用降低了死亡率，但没有一种药物能够成功治疗脓毒症 尽管进行了 100 多项介入试验，但仍被推向市场，今天的治疗方式与 60 年前一样：抗生素和 支持性护理。脓毒症很不寻常，因为大量免疫反应实际上是适应性的（有益的） 与致病（适应不良）相比，因此逆转炎症反应可以导致感染消失 未经检查。我们认为，治疗应该逆转疾病的适应不良（器官损伤）成分 免疫反应，同时保持适应性（抗病原体）成分完整。我们相信要达到 为了取得有影响力的进展，需要利用免疫亚群的新方法。在这个项目中，我们建议 将脓毒症患者细分为可治疗亚类或“内型”的精准医学方法 使用配套诊断测试 HostDx-Endotypes。我们预计将脓毒症患者分为以下几类： 内型可能使我们能够确定改进的治疗方案，从而发现新的靶标或 内型特异性治疗和/或现有药物再利用的途径。 在第一阶段的工作中，我们已经通过识别 3 种脓毒症内型（炎症性、 自适应和凝血）并在多个外部数据集上进行了验证。我们已经证明我们的 HostDx 内型可以使用多种方法将患者分为 3 篇出版物中新颖的、可能可治疗的亚组 回顾性队列和两个前瞻性队列。我们还展示了该方法的临床实用性 InSepTM 的范例，我们强大的急性传染病分类器，基于我们的 HostDx 护理点测试 系统平台。 为了将我们的概念验证工作与 HostDx-Endotypes 的产品开发联系起来，我们将（目标 1）采用 严格的机器学习算法和流程来最终确定并锁定最佳分类器； （目标 2）应用 药物再利用的创新方法，用于识别临床内型特异性候选药物并对其进行排序 关于脓毒症治疗的研究，以及（目标 3）将最终的 mRNA 组转化为 Inflammatix 的 qLAMP 盒， 平台。在第二阶段完成时，我们将共同生产 HostDx Endotypes 研究就绪盒 具有用于预期临床试验的再利用药物清单，并将准备进入正式产品 开发阶段；我们将启动 FDA 预提交。最终，该产品的目标是 将患者脓毒症内型与治疗干预明确联系起来，以便更好地选择治疗方法 和资源分配。