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) 是一种罕见的 X 连锁神经发育障碍，由 MECP2 基因突变引起。 这种疾病几乎只影响女性，因为携带 MECP2 突变的男性胎儿通常会在出生前死亡。 受影响的女性出生时表现正常；疾病发作通常在 6-18 个月时显现出来。 其特征是神经退行、运动刻板、呼吸不规则和其他临床障碍。 严重程度似乎取决于多种因素，包括 MECP2 突变的类型、X- 尽管诊断性 MECP2 基因检测可用于 MECP2 的失活和可能的遗传修饰。 RTT，RTT 的外周生物标志物，包括疾病严重程度和基于血液的微创指标 分子诊断公司 DiamiR Progress 开发了平台 基于循环分析的病理生理过程早期检测和监测技术 迄今为止在血浆中进行的富含器官（包括大脑）的 microRNA (miRNA) 的研究。 公司鉴定出有前景的 miRNA 生物标志物候选物，用于治疗神经退行性疾病和其他疾病 疾病，在这里我们建议扩展我们的技术的使用来建立 RTT 的 miRNA 生物标志物。 MECP2 的缺失会导致大脑中的突触功能障碍和 miRNA 的明显失调。 循环 miRNA 在不同的大脑区域富集，存在于突触/神经突中，并且 此外，在血浆中可检测到的可检测与 RTT 发展相关的病理生理过程。 对肝脏、肺和肌肉中富集的 miRNA 水平的分析可以反映 RTT 相关的变化 这些组织使用“miRNA 对”方法进行数据标准化，并包含候选生物标志物。 两个 miRNA 对的比例被组合成一个 miRNA 分类器以获得更高的准确性。 对四种小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 RTT 小鼠模型与野生型小鼠以及 RTT 患者与年龄匹配对照 (AMC) 区分开来； 某些 miRNA 对在小鼠和人类中是常见的，表明潜在的 miRNA 之间的相似性 目前的研究将使用在雷特中心收集的血浆样本进行。 Montefiore 医疗中心的具体目标包括：(1) 评估将 RTT 与 AMC 区分开来的可行性。 受 RTT 影响的器官/组织（脑、肝、 肺、肌肉）（60 RTT/60 AMC）；（2）评估循环 miRNA 预测疾病的潜力 通过分析先前研究的 19 种 miRNA 的血浆水平来监测疾病的严重程度和进展 3 年后从同一研究参与者（30 RTT/30 AMC）收集的纵向样本集。 SBIR II 期将涉及更大规模的临床研究，以验证 miRNA 生物标志物候选物。 最初开发为临床试验测定，并在临床数据积累后开发为体外诊断。