Long non-coding RNA signatures to distinguish relapsing-remitting multiple sclerosis from primary progressive and secondary progressive multiple sclerosis

长非编码 RNA 特征可区分复发缓解型多发性硬化症与原发性进行性和继发性进行性多发性硬化症

• 批准号: 10478749
• 负责人: Charles Floyd Spurlock
• 金额: $ 24.83万
• 依托单位: DECODE HEALTH, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-02 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10478749
• 关键词: Adverse effects; Area; Biological; Biological Markers; Biological Process; Categories; Cerebrospinal Fluid; Clinical; Clinical Data; Code; Communities; Complex; Data; Demyelinations; Detection; Diagnosis; Diagnostic; Disease; Disease Progression; Disease remission; Early treatment; Ensure; Evoked Potentials; Exhibits; Family; Gene Expression Profile; Genes; Health Personnel; Healthcare; Healthcare Systems; Human; Individual; Inflammation; Invertebrates; Investigation; Laboratories; Lead; Magnetic Resonance Imaging; Measurement; Messenger RNA; Monitor; Multiple Sclerosis; Neuraxis; Oligoclonal Bands; Organism; Outcome; Patients; Pattern; Phenotype; Primary Progressive Multiple Sclerosis; Process; Prognosis; Proteins; RNA; Randomized Clinical Trials; Recurrent disease; Relapse; Relapsing-Remitting Multiple Sclerosis; Research; Research Subjects; Rest; Secondary Progressive Multiple Sclerosis; Secondary to; Selection for Treatments; Symptoms; Testing; Therapeutic Intervention; United States; Untranslated RNA; Variant; Vertebrates; Whole Blood; advanced disease; base; care burden; cell type; clinical subtypes; cost; diagnostic tool; differential expression; disability; disease classification; disease phenotype; disorder control; effective therapy; experience; human disease; improved; ineffective therapies; multiple sclerosis patient; nervous system disorder; novel; novel diagnostics; novel therapeutics; prevent; rituximab; treatment effect; treatment planning

PROJECT SUMMARY Diagnosis and monitoring of multiple sclerosis (MS) rests on clinical symptoms and examinations as outlined in the revised McDonald criteria. These criteria are supported by appropriate magnetic resonance imaging (MRI) findings or other laboratory tests such as detection of oligoclonal bands in cerebrospinal fluid and evoked potential testing.(1-7) Approximately 10,000-15,000 new diagnoses of MS are made in the United States each year.(8) MS is classified into phenotypes depending on the patterns of demyelination of the central nervous system [CNS], inflammation and disability progression.(9) The vast majority of patients, approximately 80%- 90%, will develop a relapsing-remitting course of disease (RRMS) where symptoms develop over the course of a few days or a few months and then greatly improve or remit entirely. Up to 50% of patients with RRMS advance to secondary progressive MS (SPMS) within 10-15 years of the initial relapsing-remitting course and up to 90% of RRMS patients will transition to SPMS within 20-25 years.(10, 11) In contrast to the variations in RRMS symptoms, SPMS patients typically experience a steady progression of disease with or without relapses. Should relapses occur in SPMS, they typically do not fully remit. Early treatment with disease-modifying therapies has been shown to slow or prevent the transition of RRMS to SPMS. In addition to RRMS and SPMS, approximately 15% of patients will develop a primary progressive course of disease (PPMS) where disability progression continuously accumulates without evidence of remission. Disability in MS accrues predominantly in the progressive forms of the disease, creating a substantial health-care burden at individual, family and community levels.(10) There are more than a dozen approved therapies for RRMS.(12, 13) In contrast, only one treatment is approved to treat PPMS (ocrelizumab). Furthermore, with the exception of siponimod, approved in 2019 and investigated in the largest randomized clinical trial to date in SPMS, clinical data collected in SPMS patients treated with approved RRMS disease-modifying therapies remains an area of active investigation and debate.(10) Most clinicians commonly prescribe ocrelizumab, rituximab, or siponimod based on emerging evidence showing decreased disability.(14-16) The ability to quickly and accurately distinguish each type of MS in patients is important, as each MS subtype requires specific approaches to ensure effective treatments are prescribed and optimal clinical outcomes are achieved.(9, 17) Mischaracterization of MS can produce a significant cost burden on the healthcare system since certain approved therapies for RRMS lack evidence showing efficacy slowing SPMS or PPMS. Difficulties in identifying the correct MS phenotype can lead to patients receiving/remaining on therapies that are ineffective resulting in unnecessary costs and potential for adverse effects. As new therapies are introduced, especially those with potential neuroprotective effects for treatment progressive forms of MS, early classification of disease phenotype may represent a window of opportunity for therapeutic intervention.(9, 10, 16, 17) The cost of managing MS patients is rising and can exceed $50,000 per year. Identification of actionable biomarkers would provide clinicians with additional information for the purposes of diagnosis, prognosis, clinical subtyping and therapy selection. The question of whether or not disease classifiers capable of providing clinically useful information could be built based upon disease-specific expression levels of mRNAs in whole blood has been a subject of research for greater than ten years. Many disease-specific gene expression signatures have been identified in the research setting. Long non-coding RNAs (lncRNA) are recently discovered regulatory RNA molecules that do not code for proteins but influence a vast array of biological processes. In vertebrates, the number of lncRNA genes is thought to greatly exceed the number of protein-coding genes. It is also thought that lncRNAs drive biologic complexity observed in vertebrates compared to invertebrates. These lncRNAs also appear to show much greater cell-type specific expression patterns than mRNAs. Humans also develop many more complex diseases than other organisms. As such, our data presented in preliminary studies, support the notion that disease-associated lncRNAs exhibit far greater differences in expression than disease-associated mRNAs. In this application, we propose to explore the hypothesis that lncRNAs are better biomarkers of human disease than mRNAs. Here, we will focus on RRMS, SPMS, PPMS, and disease controls as disease categories. We will identify and validate differentially expressed lncRNAs found in each MS subtype that are capable of distinguishing among each subtype versus healthy controls as well as disease controls.

项目摘要 多发性硬化症（MS）的诊断和监测取决于临床症状和检查概述 修订后的麦当劳标准。这些标准得到适当的磁共振成像（MRI）的支持 结果或其他实验室检查，如脑脊液中寡克隆带的检测和诱发的 潜力测试(1-7)在美国，每年大约有10，000 - 15，000例MS新诊断 年(8)MS根据中枢神经脱髓鞘的模式分为表型 系统[CNS]、炎症和残疾进展。(9)绝大多数患者，大约80%- 90%，将发展为复发缓解型病程（RRMS），其中症状在病程中发展。 几天或几个月，然后大大改善或完全缓解。高达50%的RRMS患者进展 在初始复发缓解期的10-15年内，高达90%的患者发生继发性进展性MS（SPMS）， 的RRMS患者将在20-25年内过渡到SPMS。(10，11）与RRMS的变化相反， 尽管SPMS患者的症状不明显，但SPMS患者通常经历疾病的稳定进展，伴有或不伴有复发。应该 复发发生在SPMS中，它们通常不完全缓解。早期使用疾病缓解疗法进行治疗， 已被证明可以减缓或阻止RRMS向SPMS的转变。除RRMS和SPMS外， 15%的患者将发生原发性疾病进展（PPMS），其中残疾进展 持续累积而没有缓解的证据。MS中的残疾主要发生在 疾病的渐进形式，给个人、家庭和社区造成巨大的保健负担 程度.（十） 有十几种已批准的RRMS治疗方法。(12，13）相反，只有一种治疗方法是 批准用于治疗PPMS（ocrelizumab）。此外，除了2019年批准的辛波莫德外， 在迄今为止最大的SPMS随机临床试验中进行了研究，在SPMS患者中收集的临床数据 接受批准的RRMS疾病改善疗法治疗的患者仍然是一个积极研究的领域， 辩论(10)大多数临床医生通常根据出现的症状开ocrelizumab，rituximab或siponimod。 有证据表明残疾程度降低。（14-16）快速准确区分每种类型MS的能力 在患者中，这一点很重要，因为每种MS亚型都需要特定的方法来确保有效的治疗。 达到规定的和最佳的临床结果。（9，17）MS的错误表征可以产生 对医疗保健系统造成重大成本负担，因为某些获批的RRMS治疗缺乏证据 显示出减缓SPMS或PPMS的功效。 识别正确的MS表型的困难可能导致患者接受/继续接受 是无效的，导致不必要的成本和潜在的不利影响。随着新疗法的引入， 特别是那些对治疗进展型MS具有潜在神经保护作用的药物， 疾病表型的改变可能代表了治疗干预的机会之窗。（9，10，16，17）成本 管理MS患者的费用正在上升，每年可能超过50，000美元。鉴定可采取行动的生物标志物 将为临床医生提供额外的信息，用于诊断、预后、临床分型 和治疗选择。 疾病分类器是否能够提供临床有用信息的问题可能是 基于全血中mRNA的疾病特异性表达水平建立的免疫调节系统已经成为研究的主题， 超过十年。许多疾病特异性基因表达特征已在研究中被确定 设置. 长链非编码RNA（lncRNA）是最近发现的调节RNA分子， 蛋白质，但影响了大量的生物过程。在脊椎动物中，lncRNA基因的数量被认为 大大超过了蛋白质编码基因的数量。人们还认为lncRNA驱动生物复杂性， 与无脊椎动物相比，在脊椎动物中观察到。这些lncRNA似乎也显示出更大的细胞类型 比mRNAs更特异的表达模式。人类也发展出许多比其他疾病更复杂的疾病。 有机体因此，我们在初步研究中提供的数据支持了疾病相关性的概念， lncRNA表现出比疾病相关mRNA更大的表达差异。在本申请中，我们 提出探索lncRNA是比mRNA更好的人类疾病生物标志物的假设。这里我们 将侧重于RRMS、SPMS、PPMS和疾病控制作为疾病类别。我们会确认 在每种MS亚型中发现的差异表达的lncRNA能够区分每种MS亚型， 亚型与健康对照以及疾病对照。