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.

Public Health Relevance

A variety of promising new therapies are emerging for the treatment of neuromuscular disorders, including diseases such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and muscular dystrophy (DMD), as well as inflammatory myopathy. However, the testing of such therapies is hampered by the lack of powerful objective outcome measures. In this study, we assess the ability of the non-invasive technique of electrical impedance myography (EIM) in 4 different animal models each treated with its own specific therapy, to serve a therapy-response assessment tool. In addition, we evaluate how EIM outcomes relate to standard measures of function, electrophysiology, and muscle histology, helping to advance EIM's ultimate application to human clinical trials.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Skeletal Muscle and Exercise Physiology Study Section (SMEP)
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Nuckolls, Glen H
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Beth Israel Deaconess Medical Center
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