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

基本信息

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
项目类别：
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

项目摘要

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) 已成为一场全国性危机，影响超过 200 万美国人。数量过去十年，美国患有 OUD 的孕妇增加了近 5 倍，导致类似的激增出生时患有新生儿阿片戒断综合征 (NOWS) 的婴儿每 1,000 名医院新生儿中就有 1.5 至 8 名（32,000 2004 年至 2014 年间，相关医院费用上升了 35%，达到 5.32 亿美元 2014 年（其中 4.62 亿美元由医疗补助计划资助）。在产前接触非法阿片类药物的新生儿中， 55-94% 出现戒断症状，包括呼吸道、胃肠道和喂养问题。婴儿患有严重的NOWS 往往需要长期住院，2-11% 会出现严重并发症，例如癫痫发作和体重减轻。严重的病例通常需要药物干预来减轻长期不良反应足月对婴儿神经发育的影响。根据国家指南，阿片类药物使用者所生的婴儿在医院监测（72-96 小时）NOWS 迹象。然而，目前使用不同的尺度监测症状的严重程度，导致诊断不一致。此外，NOWS 还可以呈现从出生到出生后 7 天的任何时间，有时会导致出院后代价高昂的重新入院。什么时候需要采取药物措施，这些延误可能会导致婴儿发病风险增加。所以，迫切需要一种易于使用、廉价、灵敏且准确的诊断工具来支持最佳诊断患有NOWS 的婴儿的临床结果。为了满足这一需求，FYR Diagnostics 与大学一起新墨西哥州 (UNM) 和德克萨斯农工大学 (TAMU) 将开发一种方便、非侵入性的对脐带样本进行诊断分析，以早期发现严重的NOWS，以改善识别高危和低危婴儿。该检测将基于两项创新：a) miRNA 识别患有严重NOWS 的婴儿的签名； b) 正在申请专利的专有超灵敏 DNA 扩增反应 (UDAR) 化学反应使用简单的引物设计来快速、直接地检测个体低浓度的 miRNA 目前低于检测限。在第一阶段，FYR 将展示通过 1) 测试预测 miRNA 上的专有 UDAR 化学方法来验证这种新型定量工具的可行性使用 UNM/TAMU 之前使用的脐带血浆样本进行生物标记； 2) 比较 UDAR- 基于 RT-qPCR 的传统测定法，用于检测 NOWS miRNA 生物标志物以验证测定法性能并证明基于 UDAR 的检测具有同等或更高的特异性，并且敏感性。在第二阶段，FYR、UNM 和 TAMU 将进行大规模临床研究以验证NOWS 早期检测工具。临床验证研究（N=150）将评估该药物的分析和临床可行性。基于 UDAR 的检测，证明它具有与NOWS 相当的性能和预测效用 OUD 女性所生婴儿的临床变异严重程度。该项目将产生关键的 FDA 批准多中心试验所需的数据以及商业化工作的基础。