A Next Generation of Biomarkers for Incipient Huntington Disease

描述(由申请人提供)：新一代早期亨廷顿病生物标记物早期干预将有助于减缓甚至预防亨廷顿病(HD)的临床表现。为了能够进行早期干预，需要在破坏性症状出现之前跟踪疾病过程的生物标记物。多条证据表明，亨廷顿蛋白突变导致的信使和microRNAs转录失调在疾病病理生物学中起作用。虽然HD的症状反映了神经元的优先死亡，但突变的亨廷顿蛋白在周围细胞和体液中普遍表达，并可发现生化变化。这为转化为临床有用的生物标志物创造了机会。我们假设microRNAs和Messenger RNAs可以作为脑脊液和血液标记物，跟踪疾病的进展过程-在临床表型显现之前。与传统的模拟基因表达平台相比，下一代microRNA转录本测序具有更高的精确度、动态范围和灵敏度。在这里，我们将使用大规模并行测序来发现并独立复制100例患者和100名年龄和性别匹配的对照组脑脊液和血液中与显性前HD相关的所有已知和新的microRNA转录本。复制的脑脊液和血液microRNA标记物随后将被翻译到一个数字化的临床分析平台上。此外，先前与清单HD相关的信使RNA将被评估为在疾病前期的个体中用作潜在的外周生物标记物。为了为早期HD的生物标志物建立一个普遍有用的启动平台，我们将建立一个脑脊液和血液RNA生物库，与Forecast-HD相连--这是一个开发用于指导发病疾病治疗的分子标志物的全国性资源。这项研究将发现并复制生物流体转录本，这可能有助于在临床症状出现之前监测疾病过程。如果得到确认，这一点 下一代生物标记物将改变临床试验设计，并将使 有效干预。

DESCRIPTION (provided by applicant): A Next Generation of Biomarkers for Incipient Huntington's Disease Early intervention will be instrumental to slow or even prevent the clinical manifestations of Huntington's disease (HD). To enable early intervention, biomarkers are needed that track disease processes before devastating symptoms develop. Multiple lines of evidence implicate mutant huntingtin-induced transcriptional dysregulation of messenger and microRNAs in the disease pathobiology. Although HD symptoms reflect preferential neuronal death mutant huntingtin is ubiquitously expressed and biochemical changes can be found in peripheral cells and fluids. This creates an opportunity for translation into clinically useful biomarkers. We hypothesize that microRNAs and messenger RNAs can serve as cerebrospinal fluid and blood markers that track the progressive disease process --- before the clinical phenotype manifests. Next- generation sequencing of microRNA transcripts offers advantageous precision, dynamic range, and sensitivity compared to traditional analog gene expression platforms. Here we will use massively parallel sequencing to discover and independently replicate all known and novel microRNA transcripts associated with pre-manifest HD in cerebrospinal fluid and blood of 100 cases and 100 age- and sex-matched controls. Replicated cerebrospinal fluid and blood microRNA markers will then be translated onto a digital, go-to-the-clinic assay platform. Furthermore, messenger RNAs previously linked to manifest HD will be evaluated for use as potential peripheral biomarkers in individuals at pre-manifest disease stages. To build a generally useful launch platform for biological markers of incipient HD we will establish a cerebrospinal fluid and blood RNA bio-bank linked to PREDICT-HD -- a national resource for the development of molecular markers designed to guide treatment of onset disease. This study will discover and replicate bio-fluid transcripts potentialy useful for monitoring disease processes prior to the onset of clinical symptoms. If confirmed, this next generation of biomarkers will transform clinical trial design and will enable earlier and more effective intervention.