EpiXact-FMT: A metagenomic, pharmacovigilance assay for microbiota therapeutics safety

EpiXact-FMT：针对微生物群治疗安全性的宏基因组药物警戒测定

• 批准号: 10758989
• 负责人: Mohamad Sater
• 金额: $ 30万
• 依托单位: DAY ZERO DIAGNOSTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-08 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10758989
• 关键词: Address; Adopted; Adverse event; Bacteremia; Bacteria; Biological Assay; CLIA certified; Caseins; Clinical; Clinical Research; Clinical Trials; Clonality; Clostridium difficile; Complex; Data; Detection; Development; Diagnostic; Donor Selection; Ensure; Enterococcus faecium; Escherichia coli; Event; FDA approved; Feces; Foundations; Future; Gastrointestinal tract structure; Genome; Genomics; Guidelines; Human; Infection; Libraries; Link; Measures; Meta-Analysis; Metagenomics; Methods; Nucleotides; Organism; Output; Pathogenicity; Patient Transfer; Patients; Peer Review; Phase; Play; Positioning Attribute; Preparation; Protocols documentation; Recommendation; Recurrence; Refractory; Reporting; Reproducibility; Resolution; Risk; Role; Safety; Sampling; Sensitivity and Specificity; Services; Single Nucleotide Polymorphism; Standardization; Techniques; Technology; Testing; Therapeutic; Transplantation; Update; Virulent; bioinformatics pipeline; clinically relevant; communicable disease diagnosis; deep sequencing; design; detection limit; disease transmission; effective therapy; fecal microbiota; fecal transplantation; follow-up; genome sequencing; gut microbiome; gut microbiota; in silico; innovation; metagenomic sequencing; microbial; microbial community; microbial composition; microbiota; microbiota transplantation; pathogen; pharmacovigilance; prevent; prospective; prototype; risk mitigation; safety assessment; screening; transmission process; whole genome

PROJECT SUMMARY The transfer of healthy intestinal microbiota is an effective treatment for patients with refractory GI infections. Recently, FDA approved the first fecal microbiota product to prevent the recurrence of Clostridium dif- ficile infections (CDI), opening doors to other clinical trials seeking to modify intestinal microbiome. While effec- tive and generally safe, the transmission of virulent organisms is a known risk of fecal microbiota transfer (FMT). Screening of donor samples and patient surveillance are recommended to mitigate these risks, but they are neither standardized, nor comprehensive. Case-in-point, in 2019, Day Zero Diagnostics (DZD) played a crucial role in two studies, conclusively showing that transmissions do occur. As a result, FDA updated its guidelines to include (1) a more thorough follow-up of adverse events in FMT patients and (2) extended donor screening. However, there is currently no species-agnostic service that can assess donor sample safety and assist in FMT pharmacovigilance. To address this gap, DZD proposes to build epiXact-FMT – a sample prep and bioinformatic pipeline designed to provide definite answers related to FMT safety. DZD specializes in the analysis of infectious disease transmissions through whole genome sequencing (WGS)- based approaches. In the case of microbiota transfer, sequencing has the potential to assess the safety of a donor sample, but is limited by sample complexity and relating species abundance to its infectious potential. In this Phase I, DZD proposes to innovate sample preparation, deep sequencing, and SNV analysis to achieve strain-level resolution of metagenomic donor sample, which contains the genomic sequences of the entire rep- ertoire of human gut microbiota. This workflow is of immediate use for resolving suspected donor-to-patient transmissions. By measuring the genomic relatedness between the bacteria isolated from an infected patient and the same species sequenced in the complex metagenomic donor sample, DZD can rapidly determine if a patient's infection is linked to the donor. Therefore, epiXact-FMT can be directly applied in the retrospective analysis of FMT-related adverse events and pharmacovigilance. The future of microbiota transfer lies in ensuring its safety by comprehensively screening the donor samples and clearly defining a safe microbial composition and abundance. The workflow developed in this Phase I pro- posal will serve as a foundation for future prospective donor sample screening by establishing a method of pathogen (or species) detection in metagenomic samples with strain-level resolution. In the future, DZD will focus on adopting epiXact-FMT to serve as a general workflow, assessing the safety of metagenomic samples for clinical use.

项目摘要 健康肠道菌群的转移是对难治性胃肠道感染患者的有效治疗方法。 最近，FDA批准了第一个粪便菌群产物，以防止梭状芽胞杆菌的复发 易裂伤感染（CDI），开门的其他临床试验，旨在改变肠道微生物组。虽然有效 有毒生物的传播是粪便菌群转移的已知风险 （FMT）。建议对供体样本和患者监视进行筛查以减轻这些风险，但它们是 既不是标准化，也不是全面的。案例为单位，在2019年，零日诊断（DZD）播放了 在两项研究中的关键作用，最终表明确实发生了传播。结果，FDA更新了 包括（1）FMT患者不良事件和（2）延长供体的不良事件的指南。 筛选。但是，目前尚无物种不足的服务可以评估供体样本安全性和 协助FMT药物保护。为了解决这一差距，DZD提议构建Epixact-FMT - 样本准备 和生物信息学管道旨在提供与FMT安全有关的定义答案。 DZD专门研究通过整个基因组测序（WGS）的传染病传播分析 - 基于方法。在菌群转移的情况下，测序有可能评估A的安全性 供体样本，但受样本复杂性的限制，并将物种抽象与其感染潜力有关。在 该阶段I，DZD提出了创新样品制备，深入测序和SNV分析以实现的建议 宏基因组供体样品的应变水平分辨率，其中包含整个rep-的基因组序列 人类肠道微生物群的Ertoire。 该工作流程即时用于解决可疑的供体到患者的传播。通过测量 从受感染患者分离的细菌与测序的相同物种分离的细菌之间的基因组相关性 在复杂的宏基因组供体样品中，DZD可以迅速确定患者的感染是否与 捐助者。因此，epixact-fmt可以直接应用于与FMT相关不良的回顾性分析 事件和药物保护。 微生物群转移的未来在于通过全面筛选供体样品来确保其安全性 并明确定义安全的微生物组成和抽象。在此阶段发展的工作流程发展 Posal将通过建立一种方法来作为未来潜在捐助者样本筛选的基础 具有应变水平分辨率的宏基因组样品中的病原体（或物种）检测。将来，DZD将 专注于采用epixact-fmt作为一般工作流程，评估宏基因组样品的安全性 用于临床用途。