PCR-based miRNA assessment of neonatal opioid withdrawal syndrome (NOWS) severity

基于 PCR 的 miRNA 评估新生儿阿片戒断综合征 (NOWS) 严重程度

• 批准号: 10259411
• 负责人: SARJUBHAI Amratbhai PATEL
• 金额: $ 35.11万
• 依托单位: FYR DIAGNOSTICS, 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/10259411
• 关键词: Address; Affect; American; Biological Assay; Birth; Blood; Body Weight decreased; Chemistry; Clinic; Clinical; Clinical Management; Clinical Research; Clinics and Hospitals; Collaborations; Coupled; DNA amplification; Data; Detection; Development; Diagnosis; Diagnostic; Early Diagnosis; Equipment; Evaluation; Exhibits; Exposure to; Goals; Guidelines; Hospital Costs; Hospitalization; Hospitals; Hour; Incidence; Individual; Infant; Insurance; Intervention; Lead; Legal patent; Measures; Medicaid; Medication Management; Methods; MicroRNAs; Modality; Monitor; Multicenter Trials; Neonatal Abstinence Syndrome; Neurologic; New Mexico; Noise; Nucleic Acid Amplification Techniques; Nucleotides; Opioid; Outcome; Output; Performance; Pharmacological Treatment; Pharmacology; Phase; Plasma; Pregnant Women; RNA; Reaction; Reverse Transcription; Risk; Sampling; Seizures; Sensitivity and Specificity; Severities; Specificity; Symptoms; Technology; Temperature; Testing; Texas; Time; Umbilical cord structure; Universities; Withdrawal Symptom; Woman; accurate diagnostics; base; case control; commercialization; cost; design; detection assay; detection limit; diagnostic assay; feeding; fetal opioid exposure; gastrointestinal; high risk; high risk infant; hospital readmission; illicit opioid; improved; infant morbidity; infant outcome; innovation; meetings; microRNA biomarkers; neonate; noninvasive diagnosis; novel; opioid use; opioid use disorder; opioid use in pregnancy; opioid user; predictive panel; prenatal exposure; prospective; rapid test; respiratory; tool; validation studies

Abstract Opioid use disorder (OUD) has become a national crisis, affecting over 2 million Americans. The number of pregnant women with OUD in the U.S. increased almost 5-fold in the past decade, leading to a similar surge in infants born with neonatal opioid withdrawal syndrome (NOWS), from 1.5 to 8 per 1,000 hospital births (32,000 cases total) between 2004 and 2014. Associated hospital costs have risen by 35%, reaching $532 million in 2014 ($462 million of which was financed by Medicaid). Among neonates prenatally exposed to illicit opioids, 55-94% develop withdrawal symptoms, including respiratory, gastrointestinal, and feeding problems. Infants with severe NOWS often require prolonged hospitalization, and 2-11% develop serious complications, such as seizures and weight loss. Severe cases often require pharmacological intervention to mitigate negative long- term impacts on the infant's neurological development. Per national guidelines, infants born to opioid users are monitored (72-96 hours) in the hospital for signs of NOWS. However, different scales are currently in use to monitor the severity of symptoms, leading to inconsistencies in diagnosis. Moreover, NOWS can present anywhere from birth to 7 days after, sometimes leading to costly readmissions after release. When pharmacologic measures are needed, these delays can lead to an increased risk of infant morbidity. Therefore, there is an urgent need for an accessible, inexpensive, sensitive, and accurate diagnostic tool to support optimal clinical outcomes of infants with NOWS. To meet this need, FYR Diagnostics, alongside the University of New Mexico (UNM) and Texas A&M University (TAMU), will develop a convenient, non-invasive diagnostic assay from umbilical cord samples for early detection of severe NOWS to improve identification of high- and low-risk infants. The assay will be based on two innovations: a) an miRNA signature that identifies infants with severe NOWS; and b) a proprietary patent-pending ultrasensitive DNA Amplification Reaction (UDAR) chemistry that uses a simple primer design to rapidly and directly detect individual miRNAs at low concentrations currently below the limit of detection. In Phase I, FYR will demonstrate the feasibility of this novel quantitative tool by 1) testing the proprietary UDAR chemistry on predictive miRNA biomarkers using umbilical cord plasma samples previously used by UNM/TAMU; and 2) comparing the UDAR- based assay to traditional RT-qPCR-based assays for detection of NOWS miRNA biomarkers to validate assay performance and demonstrate that the UDAR-based assay exhibits equivalent or superior specificity and sensitivity. In Phase II, FYR, UNM, and TAMU will conduct a large-scale clinical study to validate the NOWS early detection tool. The clinical validation study (N=150) will evaluate the analytical and clinical feasibility of the UDAR-based assay, demonstrating that it exhibits comparable performance and predictive utility of NOWS severity across the clinical variability of infants born to women with OUD. The project will generate the pivotal data necessary for FDA approval of a multi-center trial and a basis for commercialization efforts.

抽象的 阿片类药物使用障碍（OUD）已成为一场国家危机，影响了200万美国人。数量 在过去的十年中，美国有Oud的孕妇增长了近5倍，导致类似的激增 患有新生儿阿片类药物戒断综合征（现在）的婴儿，从每1000次出生1.5到8个（32,000 案件总计2004年至2014年。相关的医院费用增加了35％，达到5.32亿美元 2014年（其中4.62亿美元由医疗补助资助）。在产前暴露于非法阿片类药物的新生儿中， 55-94％的人会出现戒断症状，​​包括呼吸道，胃肠道和进食问题。婴儿 严重的现在通常需要长时间住院，2-11％的人会出现严重的并发症，例如 癫痫发作和减肥。严重病例通常需要药理干预以减轻负长 术语对婴儿神经发展的影响有影响。根据国家准则，阿片类药物使用者出生的婴儿是 在医院监测（72-96小时），以示为NOW的迹象。但是，目前正在使用不同的尺度 监测症状的严重程度，导致诊断不一致。而且，现在可以出现 从出生到7天后，有时会导致释放后昂贵的再入院。什么时候 需要进行药理测量，这些延迟可能导致婴儿发病率的风险增加。所以， 迫切需要使用可访问，廉价，敏感和准确的诊断工具来支持最佳 现在有婴儿的临床结果。为了满足这一需求，FYR诊断与大学一起 新墨西哥州（UNM）和德克萨斯农工大学（TAMU）将发展一个方便，无创的 来自脐带样品的诊断测定，以早日检测严重的现象以改进 鉴定高风险婴儿。该测定将基于两项创新：a）mirna 识别患有严重现在的婴儿的签名； b）专有申请专利的超敏DNA 放大反应（UDAR）化学，该化学使用简单的引物设计快速并直接检测个体 低浓度的miRNA目前低于检测极限。在第一阶段，FYR将证明 通过1）测试预测性miRNA的专有UDAR化学的新型定量工具的可行性 使用UNM/TAMU先前使用的脐带等离子体样品的生物标志物； 2）比较Udar- 基于传统的RT-QPCR测定法，以检测MiRNA生物标志物以验证测定法 性能并证明基于UDAR的测定法具有等效或优越的特异性，并且 灵敏度。在第二阶段，FYR，UNM和TAMU将进行大规模的临床研究以验证现在 早期检测工具。临床验证研究（n = 150）将评估 基于UDAR OUD女性出生的婴儿的临床变异性的严重程度。该项目将产生关键 FDA批准多中心试验所需的数据以及商业化工作的基础。