Magnetic Resonance Imaging and Biomarkers for Muscular Dystrophy

项目摘要 拟议的研究是对一个长期项目的第二次竞争性更新，以开发成像 杜氏肌营养不良症(DMD)的生物标志物。提供无偏见的非侵入性结果衡量标准 在临床试验中，患者评估和可靠地评估药物反应是制定治疗方案的关键 肌肉营养不良的治疗方法。在之前的资助周期中，我们开发并验证了 动态DMD患者的定量磁共振成像(QMR)生物标志物及其模型化 疾病的轨迹在上肢和下肢肌肉。这些QMR生物标志物现在被用作主要 以及若干国际临床试验中的次要终点。 在此应用程序中，一个主要目标是通过关注患有以下疾病的老年DMD患者来扩展我们的DMD工作 晚期疾病进展。超过50%的DMD人口是非流动的，但很少有 允许将其纳入临床试验的结果衡量标准。我们建议1)发展复合型QMR 使用定量全身成像的生物标志物以及2)验证新的QMR生物标志物 呼吸肌肉质量，可以预测呼吸功能的下降，这是肌肉死亡的主要原因 营养不良。我们假设复合QMR生物标记物--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。我们会 利用目前在ImagingDMD自然历史研究中登记的大型(较老的)DMD队列来测试这些 两个新的疾病晚期QMR生物标志物。 我们还建议将我们的生物标记物开发工作扩展到Becker肌营养不良症患者。 (BMD)，疾病的较温和的等位基因形式。基因传递和外显子跳过技术的突破 导致了截短的营养不良蛋白的产生，有效地转化了DMD 表型转化为骨密度。这些治疗技术的发展有望改变下一步的格局。 一代DMD患者。因此，为了帮助未来针对dystrophin恢复的试验，我们将研究 肌营养不良蛋白表达、突变位点与QMR生物标志物的关键关系 BMD患者的质量，为跨肌肉的肌营养不良蛋白救援体内知情监测奠定了基础。 该项目解决了治疗开发中的关键障碍，并提供了一种范例的潜力 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一部分。所有自然历史数据都共享 和社区在一起。

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.