Electrical impedance myography in an animal model

项目摘要 在过去的十年里，许多治疗方法的发展取得了惊人的进步 神经肌肉疾病。有史以来第一次，治疗脊椎疾病的疗法被批准。 肌萎缩症(SMA)(Nusinesen)和Duchenne肌营养不良症(DMD)(Eteplirsen)；也是第一 肌萎缩侧索硬化症(ALS)的新疗法已被批准超过20年(依达拉奉)。许多 其他有希望的疗法也在开发中。为了测试这两种药物在临床前的疗效 在环境和人体临床试验中，反映疾病状态和对 需要治疗，因为标准的功能结果是不一致的和不敏感的。事实上，食物和 药品监督管理局(FDA)特别建立了生物标记物资格鉴定程序，以帮助加快 新疗法的测试。电阻抗肌图(EIM)是一种可能特别有价值的技术 为了这个目的。在EIM中，微小的电流通过表面电极施加到肌肉上， 测量得到的电压，提供肌肉细胞结构和组成的指数。鉴于A 许多动物和人体研究已经证明了EIM跟踪疾病进展的能力，在 为了让EIM充分发挥其潜力，提高对EIM值和EIM之间关系的理解 需要对药物效应做出反应。在R01 NS055099的最新资助期内，我们取得了 在这个方向上取得了实质性进展，探索了几种动物疾病模型中的阻抗变化 包括肌萎缩侧索硬化症、肌萎缩侧索硬化症、DMD以及骨质疏松症。在这次更新中，我们希望继续这项工作，扩大 在进一步完善EIM的科学和分析技术的同时，将其转化为治疗研究。我们的假设是 EIM将对神经肌肉疾病的各种治疗干预措施敏感 这种敏感度将超过标准的功能和生理指标。此外，我们还 假设治疗调节的组织学将导致EIM数据的特定变化 功能集。我们计划通过两个具体的目标来测试这些概念，每个目标研究两种相关的疾病类型 有文献支持的有效疗法。在目标1中，我们将研究两种神经源性疾病模型的治疗： 用Masitinib治疗SOD1G93A ALS小鼠和中度SMA小鼠模型 使用小分子脊髓运动神经元上调因子RG7800。在目标2中，我们将研究在2 肌病模型：通读化合物13治疗DBA-MDX小鼠和实验性 自身免疫性肌炎，多发性肌炎的一种模型，用雷帕霉素治疗。随着这项工程的顺利完成 研究后，我们将大大扩展我们的工具，以便在临床前和临床前有效地应用和解释EIM 动物研究和人类临床研究，帮助为其最终获得FDA资格铺平了道路。

Project Summary Over the past decade, there has been breathtaking progress in the development of therapies for many neuromuscular disorders. For the first time ever, therapies have been approved for the treatment of spinal muscular atrophy (SMA) (nusinersen) and Duchenne muscular dystrophy (DMD) (eteplirsen); also, the first new therapy in amyotrophic lateral sclerosis (ALS) has been approved in over 20 years (edaravone). Many other promising therapies are also in development. To test the efficacy of these drugs both in pre-clinical settings as well as in human clinical trials, sensitive biomarkers that reflect disease status and response to therapy are needed since standard functional outcomes are inconsistent and insensitive. In fact, the Food and Drug Administration (FDA) has specifically established a biomarker qualification process to help speed the testing of new therapies. Electrical impedance myography (EIM) is one technique that may especially valuable for this purpose. In EIM, a minute electrical current is applied to a muscle via surface electrodes and the resulting voltages measured, providing an index of a muscle's cellular structure and composition. Whereas a number of animal and human studies have already demonstrated EIM's ability to track disease progression, in order for EIM to reach its full potential, an improved understanding of the relationship between EIM values and response to drug effect is required. During the most recent funding period of R01 NS055099, we have made substantial in-roads in that direction, exploring impedance alterations in several animal disease models including ALS, SMA, DMD, as well as sarcopenia. In this renewal, we hope to continue this work, expanding into therapeutic studies, while further refining the science and analytic techniques of EIM. Our hypothesis is that EIM will be sensitive to a variety of therapeutic interventions in the neuromuscular diseases and that this sensitivity will surpass that of standard functional and physiological measures. In addition we hypothesize that the therapy-modulated histologies will cause specific alterations in the EIM data feature set. We plan to test these concepts through 2 specific aims each studying two related disease types with literature-supported effective therapies. In Aim 1, we will study treatment in 2 neurogenic disease models: the SOD1 G93A ALS mouse, treated with masitinib, and a moderate severity mouse model of SMA, treated with a small molecule spinal motor neuron upregulator, RG7800. In Aim 2, we will study treatment in 2 myopathy models: the DBA-mdx mouse treated with read-through compound 13, and experimental autoimmune myositis, a model of polymyositis, treated with rapamycin. With the successful completion of this research, we will have greatly expanded our tools to effectively apply and interpret EIM in both pre-clinical animal studies and human clinical research, helping to pave the way for its eventual FDA qualification.