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难治性胃肠道感染患者的有效宝藏。 最近，FDA批准了FIRT粪便微生物群的产物，以差异 竞争性感染（CDI），开为其他临床的门，试图改变肠道微生物组。 病毒生物的传播且通常是安全的，是粪便菌群转移的已知风险 （FMT）。 既不是标准化，也不是全面的。 在两项研究中的关键作用，最终显示了传染性的作用，因此FDA更新了ISS 包括（1）FMT患者不良事件的随访和（2）扩展供体的指南 但是，目前尚无物种敏锐的服务，可以评估供体样本安全性和 协助FMT药物宣传。 和生物信息学管道旨在提供与FMT安全有关的确定答案。 DZD专门研究整个基因组测序（WGS）的感染传播的分析 - 基于微生物群的方法，测序有可能评估 供体样本，但受样本复杂性和物种丰度与感染潜力的限制 DZD此阶段提议创新样品制备，深入测序和SNV分析以实现 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。 这种工作流程是通过测量您来解决可疑的供体转换的方法 从感染剂量分离的Bactteria与测序的相同物种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您有关 因此。 事件和药物保护。 微生物群转移的未来在于通过筛选供体样品来确保其安全性 并清楚地定义了在此阶段中开发的安全微生物组成和丰度 Posal将通过建立一种方法来作为未来潜在捐赠者样本筛查的基础 在未来的元基因组样品中检测病原体（或物种）。 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。