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志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。为了实现早期干预，需要在破坏性症状出现之前追踪疾病进程的生物标志物。多种证据暗示突变亨廷顿诱导的信使和microrna转录失调在疾病病理生物学中。虽然亨廷顿舞蹈症的症状反映了优先的神经元死亡，但突变的亨廷顿蛋白在周围细胞和液体中普遍表达，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和信使rna可以作为脑脊液和血液标记物，在临床表型显现之前跟踪疾病进展过程。与传统的模拟基因表达平台相比，下一代microRNA转录本测序提供了优势的精度、动态范围和灵敏度。在这里，我们将使用大规模平行测序来发现和独立复制所有已知的和新的microRNA转录物，这些转录物与100例患者和100例年龄和性别匹配的对照者的脑脊液和血液中显示前HD相关。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、可用于临床的检测平台上。此外，之前与显性HD相关的信使rna将被评估作为潜在的外周生物标志物在显性疾病前期的个体中使用。为了建立一个普遍有用的早期HD生物标记的启动平台，我们将建立一个脑脊液和血液RNA生物库，与PREDICT-HD相关联，PREDICT-HD是一个用于开发旨在指导发病疾病治疗的分子标记的国家资源。这项研究将发现和复制生物流体转录物，这些转录物可能有助于在临床症状出现之前监测疾病进程。如果得到证实，

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.