Magnetic Resonance Imaging and Biomarkers for Muscular Dystrophy

项目摘要 拟议的研究是一个长期项目的第二次竞争性更新，以开发成像 Duchenne肌营养不良症（DMD）的生物标志物。无创性结局指标，提供无偏倚 在临床试验中，患者评估和可靠地评价药物反应对于开发治疗性药物至关重要。 治疗肌肉萎缩症。在之前的资助周期中，我们开发并验证了下肢 非卧床DMD患者的定量磁共振成像（qMR）生物标志物， 疾病在上下肢肌肉中的轨迹。这些qMR生物标志物现在被用作主要的 和一些国际临床试验的次要终点。 在本申请中，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患者不能走动， 结果测量，允许其纳入临床试验。我们建议1）开发复合qMR 使用定量全身成像的生物标志物和2）验证评估新的qMR生物标志物 呼吸肌质量，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-最佳结合联合收割机脂肪的统计结构， 分数测量在多个肌肉-是响应在广泛的运动能力在DMD。我们将 利用目前参加ImagingDMD自然史研究的大型（老年）DMD队列来测试这些 用于晚期疾病阶段的两种新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肌营养不良症患者 (BMD)这种疾病的较温和的等位基因形式。基因传递中的断裂与外显子跳跃技术 已经导致产生可变数量的截短的肌营养不良蛋白，有效地将DMD转化为 表型转化为BMD。这些治疗方法的发展预计将改变未来的景观 DMD患者的一代。因此，为了帮助未来的试验靶向肌营养不良蛋白的恢复，我们将研究 肌营养不良蛋白表达、突变位点与肌肉qMR生物标志物之间的重要关系 BMD患者的质量，为肌营养不良蛋白在肌肉中的拯救的体内监测奠定基础。 该项目解决了治疗发展中的关键障碍，并提供了一个范例的潜力。 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治疗提供信息 并将解决DMD中翻译基因恢复中缺失的部分。所有的自然历史数据都是共享的 与社区的关系。

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.