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.

项目总结 移植健康的肠道微生物群是治疗难治性胃肠道感染的有效方法。 最近，FDA批准了第一个防止DIF梭菌复发的粪便微生物区系产品。 非淋巴感染(CDI)，为寻求改变肠道微生物群的其他临床试验打开了大门。当有效的时候- 有害生物的传播通常是安全的，这是粪便微生物群转移的已知风险。 (FMT)。建议对捐献者样本进行筛查和患者监测以降低这些风险，但它们 既不规范，也不全面。案例，2019年，零日诊断(DZD)发挥了作用 在两项研究中发挥了关键作用，最终表明确实发生了传播。因此，FDA更新了其 指导方针包括：(1)对FMT患者的不良事件进行更彻底的随访；(2)扩大供者范围 放映。然而，目前还没有物种不可知的服务机构来评估捐赠者样本的安全性和 协助FMT药物警戒。为了弥补这一差距，DZD建议构建epexact-fmt-a Sample Prep 以及生物信息学管道，旨在提供与FMT安全相关的明确答案。 DZD专门通过全基因组测序(WGS)分析传染病传播- 基于方法。在微生物群转移的情况下，测序有可能评估一种 捐赠者样本，但受到样本复杂性和物种丰度与其感染潜力的关系的限制。在……里面 在这一阶段，DZD建议创新样品准备、深度测序和SNV分析，以实现 后基因组供体样本的应变水平分辨率，它包含整个代表的基因组序列。 人类肠道微生物区系的EROTORE。 这一工作流程可立即用于解决疑似捐赠者对患者的传播问题。通过测量 从感染患者分离的细菌与同种细菌的基因组相关性 在复杂的元基因组供体样本中，DZD可以快速确定患者的感染是否与 捐赠者。因此，EPXact-FMT可直接用于FMT相关不良反应的回顾性分析 事件和药物警戒。 微生物区系转移的未来在于通过全面筛选供体样本来确保其安全性 并明确界定安全的微生物组成和丰度。在此第一阶段中开发的工作流程- POSAL将作为未来潜在捐赠者样本筛选的基础，通过建立一种方法 用菌株水平分辨率检测元基因组样本中的病原体(或物种)。未来，DZD将 重点采用epxact-FMT作为一般工作流程，评估元基因组样本的安全性 供临床使用。