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: 10462722
• 负责人: Timothy E Sweeney
• 金额: $ 101.8万
• 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/10462722
• 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; diagnostic tool; drug action; drug candidate; drug repurposing; fighting; genetic signature; immunoregulation; improved; innovation; machine learning algorithm; machine learning classifier; machine learning pipeline; 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; 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 败血症是一种全身性炎症状况，是作为感染并发症而发生的，在严重情况下可能是 与急性和威胁生命的器官功能障碍有关。仅在美国，败血症就宣称约有270,000个生命 在每年诊断出的约170万患者中，在全球范围内，与败血症相关的死亡率估计为 占总死亡的20％。尽管改善了败血症和及时的治疗方案 抗生素的给药降低了死亡率，败血症的单一药物从未成功 购买到市场，目的地超过100次介入试验，今天被视为60年前：抗生素和 支持护理。败血症是不寻常的，因为大量免疫反应实际上是适应性的（有益的） 与致病性疾病（适应不良），因此逆转炎症反应会导致感染发生 未选中。我们认为，治疗应扭转适应不良（器官破坏）的成分 免疫反应，同时保持适应性（病原体抗病）成分完整。我们相信要实现 在这个项目中，我们建议 一种细分败血症患者的精确医学方法 使用伴侣诊断测试，hostdx-构型。我们预计将败血症患者分类为 内型可能使我们能够确定改进的治疗方案，从而发现新目标或 可用药物的内型特异性疗法和/或重新利用的途径。 在第1阶段的工作中，我们已经通过识别3种败血症（炎症，炎症，， 自适应和凝结性），并在多个外部数据集中进行了验证。我们已经证明了我们的hostdx 内型可以使用几个出版物将患者分为新颖的，潜在的可治疗亚组 回顾性队列和两个前瞻性队列。我们还证明了这一点的临床实用性 根据我们的HOSTDX护理点测试 系统平台。 为了弥合概念证明的工作，以供hostdx-endypes的产品开发，我们将（AIM 1）采用 严格的机器学习算法和过程，以最终确定和锁定最佳分类器； （AIM 2）应用 药物重新利用的创新方法，以识别和等级内型内型特异性药物候选临床的候选药物 败血症治疗的研究，（目标3）将最终的mRNA面板转换为炎症的Qlamp弹药筒和 平台。在第二阶段完成时，我们将共同生产HostDX Endotypes Research Research Retridge，一起 列出了预期临床试验的重新利用药物，并准备进入正式产品 发展阶段；我们将启动FDA预提取。最终，该产品的目标是 确切地将患者败血症内型与治疗干预联系起来，以实现更好的治疗选择 和资源分配。