Electrical impedance myography and quantitative ultrasound in Duchenne muscular d

描述(申请人提供)：Duchenne肌营养不良症(DMD)是最常见的儿童神经肌肉疾病之一，影响大约3500名活产男婴中的1名，导致进行性肌肉无力，并使患者在大约12岁时被轮椅束缚，死亡发生在生命的第三个十年。在过去的20年里，在理解疾病发病机制的基本机制方面取得了很大进展，并开发了许多新的潜在治疗策略，从外显子跳过方法到干细胞疗法。疾病治疗选择范围的扩大也极大地增加了对改进方法的需求，以加快对第二阶段和第三阶段临床试验中有希望的药物的评估。目前使用的生物标记物，如6分钟步行试验，对变化相对不敏感，需要临床试验来招募大量受试者，同时仍有能力检测往往过于乐观的治疗效果。两种高度创新、易于应用、基于办公室的无痛方法在作为疾病进展的新的、敏感的标记方面具有巨大的前景，这两种方法是电阻抗肌图(EIM)和定量超声(QUS)。在EIM中，通过表面电极施加微弱的高频电流，并测量随后的表面电压图案的变化。在QUS中，使用标准设备获得的超声图像被提炼成可用于量化疾病严重程度的数字数据。这可以通过使用用于校准的体模的后处理图像分析或通过减少原始后向散射声数据来实现。在这项拟议的工作中，我们将独立研究EIM和QUS，以评估它们在DMD试验中的潜在用途。具体地说，我们将通过对35名正常受试者和35名5至12岁患有DMD的男孩进行为期两年的跟踪研究来实现这一点。在具体目标1中，我们将立即和在几天时间内确定这两种技术的可重复性。在具体目标2中，我们将评估EIM和QUS随时间的变化的临床意义，方法是将它们的进展率与两年内的功能测量结果进行比较。在具体目标3中，我们将评估这两种方法在很短的时间内(1至2个月)检测疾病进展的能力，以及进展速度对长期功能变化的预测能力。作为我们计划的探索性分析的一部分，我们还将评估将EIM和QUS数据集融合为单一复合生物标记物的方法，以及随着时间的推移在EIM数据中跟随收缩引起的变化的潜在价值。随着这项工作的成功完成，我们将为在DMD第二阶段临床试验中使用其中一种或两种技术作为首选生物标记物奠定基础。

DESCRIPTION (provided by applicant): Duchenne muscular dystrophy (DMD) is one of the most common neuromuscular diseases of children affecting approximately 1 in 3500 live male births, producing progressive muscle weakness and leaving affected individuals wheelchair bound by approximately 12 years of age with death occurring by the third decade of life. Over the past 20 years great inroads have been made into understanding the basic mechanisms underlying disease pathogenesis and many new potential therapeutic strategies have been developed, ranging from exon-skipping methodologies to stem cell therapies. This expanding range of disease treatment options has also greatly increased the need for improved methods to speed the assessment of promising drugs in Phase II and Phase III clinical trials. The current biomarkers that are employed, such as the 6-minute walk test, are relatively insensitive to change and require clinical trials to enroll large numbers of subjects while still being powered to detect an often overly optimistic treatment effect. Two highly innovative, easily applied, office-based, painless methodologies that offer great promise in serving as novel, sensitive markers of disease progression, are electrical impedance myography (EIM) and quantitative ultrasound (QUS). In EIM, a weak, high-frequency electrical current is applied via surface electrodes and alterations in the consequent surface voltage pattern are measured. In QUS, ultrasound images obtained using standard devices are distilled down to numerical data that can be used to quantify disease severity. This can be accomplished either via post-processing image analysis with use of a phantom for calibration or via a reduction of the raw backscattered acoustic data. In this proposed work, we will study both EIM and QUS independently to assess their potential use in DMD trials. Specifically we will do this by studying a group of 35 normal subjects and 35 boys with DMD aged 5 to 12 years followed for a 2-year period of time. In Specific Aim 1, we will establish the repeatability of both techniques both immediately and over several days time. In Specific Aim 2, we will assess the clinical significance of alterations in both EIM and QUS over time by comparing their rate of progression to that seen with functional measures out to two years. In Specific Aim 3, we will assess the ability of both measures to detect disease progression over very short periods of time-1 to 2 months-and how well that rate of progression predicts long-term functional change. As part of our planned exploratory analyses, we will also assess approaches for fusing EIM and QUS data sets into single composite biomarkers and the potential value of following contraction-induced alterations in the EIM data over time. With the successful completion of this work, we will have set the stage for the use of one or both of these techniques as the preferred biomarkers in Phase II clinical trials in DMD.