Progression and Biomarkers of DM1

DM1 的进展和生物标志物

• 批准号: 9344684
• 负责人: RICHARD T MOXLEY
• 金额: $ 45.89万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9344684
• 关键词: 3' Untranslated Regions; Adopted; Affect; Alleles; Alternative Splicing; Binding; Biological; Biological Markers; Biopsy Specimen; Clinical; Clinical Research; Clinical Trials; Collaborations; Data; Defect; Development; Disease; Disease Progression; Distal; Effectiveness; Evaluation; Event; Fostering; Freezing; Generations; Genetic; Genetic Determinism; Genetic Polymorphism; Goals; Hand; Impairment; Individual; Industry; Instruction; Interruption; Length; Measurement; Measures; Mediating; Medicine; Molecular; Monitor; Motor; Multicenter Studies; Mus; Muscle; Muscle Weakness; Muscular Dystrophies; Mutation; Myopathy; Myotonia; Myotonic Dystrophy; Needle biopsy procedure; New Agents; Other Genetics; Outcome; Outcome Measure; Pathogenesis; Patient Outcomes Assessments; Patients; Pharmaceutical Preparations; Physiological; Population Heterogeneity; Preparation; Procedures; Process; RNA; RNA Splicing; RNA marker; Readiness; Regulation; Relaxation; Research; Research Personnel; Sampling; Severities; Severity of illness; Site; Standardization; Testing; Therapeutic Trials; Time; Tissues; Toxic effect; Validation; Work; base; candidate marker; cohort; design; drug development; effectiveness clinical trial; follow-up; grasp; molecular targeted therapies; mutant; novel therapeutics; response; skeletal; targeted treatment; therapeutic development; therapeutic target; tibialis anterior muscle; time use; tool; treatment response; trial design; vastus lateralis; whole genome

PROJECT SUMMARY (See instructions):� Myotonic dystrophy type 1 (DM1) is one of the most variable diseases known to medicine. Research on this disorder has led to the recognition of RNA toxicity, a new paradigm for muscle disease. The mutation in DMl, an expanded CTG repeat in the 3' untranslated region of DMPK, is genetically unstable. Increases of CTG expansion size in subsequent generations are associated with greater severity of disease. Deleterious effects of the expansion are mediated by mutant RNA, which contains an expanded CUG repeat. Splicing factors that bind to CUG expansions are sequestered, which leads to abnormal regulation of alternative splicing. Recognition of this mechanism has fostered the development of targeted therapies for DM1. As new treatments advance into clinical trials, there is a compelling need for clinical endpoints that are reliable and sensitive indicators of the therapeutic response. The process of testing new agents will be greatly assisted by the availability of biomarkers that accurately reflect drug activity in muscle tissue. Furthermore, it is increasingly important to understand the biological basis for DM1 variability, because this may confound clinical outcomes or impact the individual response to targeted therapies. We have found that some individuals with very large CTG expansions in muscle tissue do not exhibit severe muscle weakness, suggesting that genetic factors other than expansion size may influence DM1 severity. Aim 1 of this project will quantify longitudinal changes of DM1 across a wide spectrum of patients, and identify endpoints that are sensitive for detecting disease progression. Aim 2 will determine whether it is feasible to monitor splicing defects in muscle tissue in multicenter studies. We also plan to qualify a group of splicing events as biomarkers of DM1 severity. Aim 3 will standardize myotonia assessment as a physiological indicator of RNA toxicity. Aim 4 will test the hypothesis that CTG expansion length is not a unitary explanation for DM1 severity. Genetic modifiers of DM1 will be sought, first by examining a candidate locus and then by testing for associations across the entire genome. Overall, this project will supply critical information that is needed to move forward with therapeutic development in DM1.

项目摘要（参见说明）：� 强直性肌营养不良1型(DM1)是医学上已知的最易变的疾病之一，对这种疾病的研究导致了对RNA毒性的认识，这是肌肉疾病的新范例。DM1中的突变是3中扩展的CTG重复。 DMPK 的非翻译区在遗传上不稳定，后续世代中 CTG 扩增大小的增加与包含扩增的 CUG 重复序列的突变 RNA 介导的扩增的有害影响有关。与 CUG 扩增结合的剪接因子被隔离，导致选择性剪接的异常调节。随着新疗法进入临床试验，迫切需要能够实现这一点的临床终点。是治疗反应的可靠且敏感的指标，准确反映肌肉组织中药物活性的生物标志物的可用性将极大地帮助测试新药物的过程，因为了解 DM1 变异的生物学基础变得越来越重要。这可能会混淆临床结果或影响个体对靶向治疗的反应我们发现，一些肌肉组织中 CTG 扩张非常大的个体不会表现出严重的肌肉无力，这表明除了扩张大小之外的遗传因素可能会影响 DM1 的严重程度。该项目的目标将量化广泛患者中 DM1 的纵向变化，并确定对检测疾病进展敏感的终点。目标 2 将确定在多中心研究中监测肌肉组织的剪接缺陷是否可行。有资格目标 3 将一组剪接事件标准化为 RNA 毒性的生理指标，即 CTG 扩增长度不是 DM1 严重程度的统一解释。总体而言，该项目将提供推进 DM1 治疗开发所需的关键信息。