Electrical impedance myography in an animal model

项目摘要 在过去的十年里，许多人的治疗方法取得了惊人的进展。 神经肌肉疾病有史以来第一次，治疗方法已被批准用于治疗脊柱 肌萎缩症（SMA）（nusinersen）和杜氏肌营养不良症（DMD）（eteplirsen）;此外， 肌萎缩性侧索硬化症（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。为了测试这些药物在临床前 以及在人类临床试验中，反映疾病状态和对 由于标准功能结果不一致且不敏感，因此需要治疗。事实上，食物和 美国药品监督管理局（FDA）专门建立了一个生物标志物的资格认证过程，以帮助加快 测试新疗法。电阻抗肌电描记术（EIM）是一种特别有价值的技术， 为此目的。在EIM中，通过表面电极向肌肉施加微小电流， 测量产生的电压，提供肌肉的细胞结构和组成的指数。而一个 许多动物和人体研究已经证明了EIM跟踪疾病进展的能力， 为了使EIM充分发挥其潜力，需要更好地理解EIM值与 需要对药物作用作出反应。在R 01 NS 055099的最新资助期间，我们已经取得了 在这个方向上取得了实质性的进展，探索了几种动物疾病模型中的阻抗变化 包括ALS、SMA、DMD以及肌肉减少症。在这次更新中，我们希望继续这项工作，扩大 治疗研究，同时进一步完善EIM的科学和分析技术。我们的假设是 EIM将对神经肌肉疾病的各种治疗干预敏感， 这种灵敏度将超过标准的功能和生理测量。此外我们 假设治疗调节的组织学将导致EIM数据的特定改变 功能集。我们计划通过两个特定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2种神经源性疾病模型的治疗： 用马赛替尼治疗的SOD 1 G93 A ALS小鼠和用马赛替尼治疗的中度严重SMA小鼠模型 与一种小分子脊髓运动神经元上调剂RG 7800一起。在目标2中，我们将研究2 肌病模型：用通读化合物13处理的DBA-mdx小鼠，和实验性肌病模型。 自身免疫性肌炎，多发性肌炎模型，用雷帕霉素治疗。随着这一项目的成功完成， 研究，我们将极大地扩展我们的工具，以有效地应用和解释EIM在临床前 动物研究和人体临床研究，为最终获得FDA认证铺平道路。

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.