Magnetic Resonance Imaging and Biomarkers for Muscular Dystrophy

肌营养不良症的磁共振成像和生物标志物

• 批准号: 10466943
• 负责人: KRISTA H VANDENBORNE
• 金额: $ 123.72万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-05 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10466943
• 关键词: 9 year old; Abdomen; Address; Age; Alleles; Becker Muscular Dystrophy; Biological Markers; Biopsy; Cause of Death; Chest wall structure; Cine Magnetic Resonance Imaging; Clinical Trials; Clinical Trials Design; Clinical assessments; Communities; Data; Disease; Disease Progression; Disease model; Duchenne muscular dystrophy; Dystrophin; Enrollment; Europe; Exhibits; Fatty acid glycerol esters; Funding; Future; Gene Delivery; Genes; Genetic; Goals; Histologic; Image; Impairment; Individual; Infiltration; Inflammation; International; Leg; Lower Extremity; Magnetic Resonance Imaging; Measures; Molecular; Monitor; Motor; Multi-Institutional Clinical Trial; Multicenter Studies; Muscle; Muscle Weakness; Muscular Atrophy; Muscular Dystrophies; Mutation; Natural History; Outcome Measure; Patients; Pelvic Girdle; Pharmaceutical Preparations; Phenotype; Population; Positioning Attribute; Production; Protocols documentation; Reproducibility; Research; Research Design; Respiratory Diaphragm; Respiratory Failure; Respiratory Muscles; Respiratory physiology; Site; Technology; Testing; Upper Extremity; Wasting Syndrome; Work; advanced disease; arm; arm function; base; biomarker development; chromosome X loss; cohort; curative treatments; data sharing; exon skipping; experience; imaging biomarker; in vivo monitoring; magnetic resonance imaging biomarker; next generation; novel; predictive marker; primary endpoint; pulmonary function; respiratory; response; restoration; secondary endpoint; therapeutic development; whole body imaging

Project Summary The proposed research is for the second competitive renewal of a long-term project to develop imaging biomarkers for Duchenne muscular dystrophy (DMD). Noninvasive outcome measures that provide unbiased patient assessments and reliably evaluate drug responses in clinical trials are essential to develop curative therapies for muscular dystrophies. In the previous funding cycles, we developed and validated lower extremity quantitative magnetic resonance imaging (qMR) biomarkers for ambulatory patients with DMD and modeled the disease trajectory in upper and lower extremity muscles. These qMR biomarkers are now used as primary and secondary endpoints in a number of international clinical trials. In this application one major objective is to extend our DMD work by focusing on older DMD patients with advanced disease progression. More than 50% of the DMD population is nonambulant, yet there are few outcome measures that permit their inclusion in clinical trials. We propose to 1) develop composite qMR biomarkers using quantitative whole-body imaging and 2) validate novel qMR biomarkers that assess respiratory muscle quality and can predict a decline in respiratory function, a major cause of death in muscular dystrophies. We hypothesize that composite qMR biomarkers–statistical constructs that optimally combine fat fraction measures in multiple muscles–are responsive across a wide range of motor abilities in DMD. We will leverage the large (older) DMD cohort currently enrolled in the ImagingDMD natural history study to test these two new qMR biomarkers for advanced disease stages. We also propose to extend our biomarker development work to patients with Becker muscular dystrophy (BMD), the milder allelic form of the disease. Breakthroughs in gene delivery and exon skipping technology have resulted in production of truncated dystrophin in variable amounts, effectively converting the DMD phenotype into BMD. These therapeutic developments are expected to change the landscape for the next generation of DMD patients. Thus, to assist future trials targeting dystrophin restoration, we will examine the critical relationship between dystrophin expression, mutation site and qMR biomarkers of muscle quality in BMD patients, setting the stage for informed in vivo monitoring of dystrophin rescue across muscles. This project addresses critical barriers in therapeutic development and provides the potential for a paradigm shift in clinical trial design in DBMD. In addition, this project will help inform future molecular based therapies and will address a missing piece in translational gene restoration in DMD. All natural history data are shared with the community.

项目概要 拟议的研究是为了开发成像的长期项目的第二次竞争性更新 杜氏肌营养不良症 (DMD) 的生物标志物。提供公正的非侵入性结果测量 在临床试验中对患者进行评估并可靠地评估药物反应对于开发治疗方法至关重要 肌肉营养不良症的治疗方法。在之前的融资周期中，我们开发并验证了下肢 动态 DMD 患者的定量磁共振成像 (qMR) 生物标志物并建模 上肢和下肢肌肉的疾病轨迹。这些 qMR 生物标志物现在被用作主要的 以及许多国际临床试验中的次要终点。 在此应用中，一个主要目标是通过关注老年 DMD 患者来扩展我们的 DMD 工作。 晚期疾病进展。超过 50% 的 DMD 人群无法行走，但只有少数人 允许将其纳入临床试验的结果衡量标准。我们建议 1) 开发复合 qMR 使用定量全身成像的生物标志物，2) 验证评估新的 qMR 生物标志物 呼吸肌质量，并可以预测呼吸功能的下降，呼吸功能的下降是肌肉发达的死亡的主要原因 营养不良。我们假设复合 qMR 生物标志物——最佳结合脂肪的统计结构 多块肌肉的分数测量——对 DMD 的各种运动能力都有反应。我们将 利用目前参加 ImagingDMD 自然历史研究的大型（较旧）DMD 队列来测试这些 两种用于晚期疾病阶段的新 qMR 生物标志物。 我们还建议将我们的生物标志物开发工作扩展到贝克尔肌营养不良症患者 (BMD)，该疾病的较温和等位基因形式。基因传递和外显子跳跃技术的突破 导致产生不同数量的截短肌营养不良蛋白，有效地转化 DMD 表型转化为 BMD。这些治疗进展预计将改变未来的前景 DMD 患者的一代。因此，为了帮助未来针对肌营养不良蛋白恢复的试验，我们将检查 肌营养不良蛋白表达、突变位点和肌肉 qMR 生物标志物之间的关键关系 BMD 患者的质量，为跨肌肉的肌营养不良蛋白救援的体内监测奠定了基础。 该项目解决了治疗开发中的关键障碍，并提供了范例的潜力 DBMD 临床试验设计的转变。此外，该项目将有助于为未来的分子疗法提供信息 并将解决 DMD 翻译基因恢复中缺失的部分。所有自然历史数据都是共享的 与社区。