A Next Generation of Biomarkers for Incipient Huntington Disease

描述（申请人提供）：早期亨廷顿病的下一代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。为了能够进行早期干预，需要生物标志物在破坏性症状出现之前跟踪疾病过程。多种证据表明突变亨廷顿蛋白诱导的信使和microRNA转录失调在疾病病理学。虽然HD症状反映了优先神经元死亡，但突变型亨廷顿蛋白普遍表达，并且可以在外周细胞和体液中发现生化变化。这为转化为临床有用的生物标志物创造了机会。 我们假设microRNA和信使RNA可以作为脑脊液和血液标记物，在临床表型出现之前跟踪疾病的进展过程。与传统的类似基因表达平台相比，microRNA转录物的下一代测序提供了有利的精度、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并独立复制100例病例和100例年龄和性别匹配对照的脑脊液和血液中与预表现HD相关的所有已知和新的microRNA转录物。复制的脑脊液和血液microRNA标记物将被翻译到数字化的临床检测平台上。此外，将评估先前与显性HD相关的信使RNA，以用作处于疾病表现前阶段的个体的潜在外周生物标志物。为了建立一个普遍有用的早期HD生物标志物的启动平台，我们将建立一个与PREDICT-HD相关的脑脊液和血液RNA生物库，PREDICT-HD是一个用于开发分子标志物的国家资源，旨在指导发病疾病的治疗。 这项研究将发现和复制生物流体转录本潜在有用的监测疾病的过程之前，临床症状的发作。如果得到证实， 下一代生物标志物将改变临床试验设计， 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.