Circulating Organ-enriched microRNAs as biomarkers of Rett Syndrome

富含循环器官的 microRNA 作为 Rett 综合征的生物标志物

• 批准号: 10267164
• 负责人: SAMUIL R UMANSKY
• 金额: $ 11.1万
• 依托单位: DIAMIR, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2023-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10267164
• 关键词: 15 year old; Affect; Age; Animal Model; Animals; Biological Assay; Biological Markers; Biological Sciences; Birth; Blood; Brain; Brain region; Breathing; Characteristics; Cholesterol; Clinical; Clinical Data; Clinical Research; Clinical Trials; Data; Development; Diagnostic; Differential Diagnosis; Disease; Disease Progression; Early Diagnosis; Enzymes; Female; Fetus; Functional disorder; Gait; Genes; Genetic; Goals; Growth; Human; Impairment; Link; Liver; Lung; Measures; Medical center; Metabolic; Metabolism; Methyl-CpG-Binding Protein 2; MicroRNAs; Microcephaly; Modeling; Molecular; Monitor; Motor; Mus; Muscle; Mutation; Nerve Degeneration; Neurites; Neuritis; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurologic; Onset of illness; Organ; Participant; Pathologic Processes; Pathology; Patients; Peripheral; Phase; Pilot Projects; Plasma; Process; Prognosis; Regimen; Research Personnel; Rett Syndrome; Sampling; Seizures; Sensitivity and Specificity; Severities; Severity of illness; Small Business Innovation Research Grant; Staging; Structure of parenchyma of lung; Symptoms; Synapses; System; Technology; Therapeutic; Tissues; Wild Type Mouse; X Inactivation; age group; base; candidate marker; circulating microRNA; commercial application; gastrointestinal; genetic testing; human study; in-vitro diagnostics; knowledge base; lipid metabolism; liver metabolism; male; microRNA biomarkers; minimally invasive; molecular diagnostics; mouse model; muscle metabolism; participant enrollment; stereotypy; therapeutic development

SUMMARY Rett syndrome (RTT) is a rare X-linked neurodevelopmental disorder caused by mutations in the MECP2 gene. The disease affects females almost exclusively, since male fetuses with a MECP2 mutation usually die before birth. Affected females appear normal at birth; disease onset is typically evident by 6-18 months and is characterized by neurological regression, motor stereotypies, irregular breathing, and other handicaps. Clinical severity appears to depend on multiple factors, including the type of MECP2 mutation, skewing of the X- inactivation and likely genetic modifiers of MECP2. Although diagnostic MECP2 genetic testing is available for RTT, peripheral biomarkers of RTT, including minimally invasive, blood-based indicators of disease severity and progression, are lacking. DiamiR, a molecular diagnostics company, has developed proprietary platform technology for early detection and monitoring of pathophysiological processes based on analysis of circulating organ-enriched, including brain-enriched, microRNAs (miRNAs) in plasma. Studies conducted to date at the company resulted in identification of promising miRNA biomarker candidates for neurodegenerative and other diseases, and here we propose extending the use of our technology to establish miRNA biomarkers of RTT. Loss of MECP2 results in synaptic dysfunction and marked dysregulation of miRNAs in the brain. We hypothesize that circulating miRNAs enriched in different brain regions, present in synapses/neurites, and detectable in plasma can detect pathophysiological processes associated with RTT development. In addition, analysis of levels of miRNAs enriched in liver, lung and muscle can be reflective of RTT associated changes in these tissues. An “miRNA pair” approach is used for data normalization, and a biomarker candidate is comprised of a ratio of two miRNAs. Two-three miRNA pairs are combined into a miRNA classifier for higher accuracy. Preliminary studies performed with four murine models and human patients identified miRNA pairs and classifiers differentiating both RTT mouse models from wild-type mice and RTT patients from age-matched control (AMC); certain miRNA pairs were common to mice and humans, indicating the similarity between the underlying pathological processes. The current study will be performed using plasma samples collected at the Rett Center at Montefiore Medical Center. Specific aims include: (1) assessing the feasibility of differentiating RTT from AMC by plasma levels of 38 pre-selected circulating miRNAs enriched in organs/tissues affected by RTT (brain, liver, lung, muscle) (60 RTT/60 AMC); and (2) evaluating the potential of circulating miRNAs for predicting disease severity and monitoring disease progression by analysis of plasma levels of the previously studied 19 miRNAs in the longitudinal set of samples collected 3 years later from the same study participants (30 RTT/30 AMC). SBIR Phase II will involve larger clinical studies to validate miRNA biomarker candidates. The assay will be initially developed as a clinical trial assay, and, upon accumulation of clinical data, as in vitro diagnostics.

概括 RETT综合征（RTT）是由MECP2基因突变引起的一种罕见的X连锁神经发育障碍。 该疾病几乎完全影响女性，因为具有MECP2突变的雄性胎儿通常会在 出生。受影响的雌性在出生时看起来正常。疾病发作通常在6-18个月中证明 以神经系统回归，运动刻板印象，不规则的呼吸和其他障碍为特征。临床 严重程度似乎取决于多种因素，包括MECP2突变的类型，X-的偏斜 MECP2的失活和可能的遗传修饰符。尽管可以使用诊断MECP2基因检测 RTT，RTT的周围生物标志物，包括微创，基于血液的疾病严重程度和 进展，缺乏。分子诊断公司Diamir已开发了专有平台 基于循环分析的病理生理过程的早期检测和监测技术 富含器官，包括血浆中的脑含有脑部的microRNA（miRNA）。迄今为止进行的研究 公司导致确定有希望的miRNA生物标志物候选神经退行性和其他 疾病，我们在这里提议扩展使用技术来建立RTT的miRNA生物标志物。 MECP2的丧失会导致突触功能障碍和大脑中miRNA的明显失调。我们 假设富含不同大脑区域的循环miRNA，存在于突触/神经突和 在血浆中可检测可以检测与RTT发育相关的病理生理过程。此外， 分析富含肝脏，肺和肌肉的miRNA水平可以反映RTT相关的变化 这些组织。 “ miRNA对”方法用于数据归一化，并完成了生物标志物候选者 两个miRNA的比例。将两个三分的miRNA对组合成miRNA分类器，以提高精度。 对四个鼠模型和人类患者进行的初步研究确定了miRNA对和分类器 将两种RTT小鼠模型与野生型小鼠和RTT患者与年龄匹配对照（AMC）区分开； 某些miRNA对是小鼠和人类共同的，表明基础之间的相似性 当前的研究将使用RETT中心收集的血浆样本进行 在蒙特菲奥尔医疗中心。具体目的包括：（1）评估将RTT与AMC区分开的可行性 通过血浆水平的38个预选的循环miRNA，富含RTT影响的器官/组织（脑，肝脏， 肺，肌肉）（60 RTT/60 AMC）; （2）评估循环miRNA预测疾病的潜力 严重性和通过分析先前研究的19个miRNA的血浆水平分析来监测疾病的进展 在3年后从同一研究参与者（30 RTT/30 AMC）收集的样品纵向集中。 SBIR II期将涉及较大的临床研究，以验证miRNA生物标志物候选物。测定将是 最初是作为临床试验测定法而开发的，并且在临床数据的积累后，作为体外诊断。