High Content Screening for Muscular Dystrophy

DESCRIPTION (provided by applicant): Duchenne Muscular Dystrophic (DMD) is a fatal genetic disease affecting tens of thousands of boys in the U.S. There is currently no cure for the disease and few drugs are available to slow the progressive loss in skeletal muscle strength. Glucocorticoids such as prednisone are one of the few classes of drugs in clinical use in DMD to slow the loss of muscle function, but have serious adverse side effects when used chronically. There is thus a great need to identify new compounds that can improve the longevity and quality of life of the boys with this devastating disease. Myomics has developed a phenotypic high content drug screening technology termed MyoForce Analysis System (MFASTM). It is comprised of tissue engineered skeletal muscle (Miniature BioArtificial Muscles or mBAMs) attached to micro-mechanical sensors in ninety-six microwell plates to quantitatively measure muscle contractile forces. These three-dimensional contractile tissues are composed of organized striated skeletal muscle fibers that generate directed force when electrically stimulated. Myomics' mBAM tissue/sensor composite is capable of repetitive nondestructive force measurements over days to weeks. Such long-term studies can determine cumulative effects of drugs on tissues and provides physiological data regarding tissue function. The physiological measurement of force generation by mBAMs is not limited to any particular known biochemical pathway, but rather the measurement of force is the result of both positive and negative drug effects. Thus, MFASTM will not only screen compounds for positive muscle strength effects through known as well as unknown pathways, but will more rapidly eliminate target compounds with potentially adverse side effects. In Myomics' Phase I SBIR project mBAMs were tissue engineered from conditionally immortalized myoblasts from the mdx mouse, the small animal model of DMD. These dystrophin negative mBAMs generated measureable tetanic forces that increased significantly when incubated with nine compounds that improve muscle strength in vivo. MFASTM was thus validated as a screen for new drugs to treat muscle weakness in DMD and will serve as an important bridge between target-based high throughput drug screening and follow-on in vivo animal studies; it provides a rapid and cost effective screen compared to in vivo testing. The purpose of this Phase II project is to (1) Screen commercially available banks of clinically tested small molecules (600-1200) for increased skeletal muscle strength; and (2) Determine whether compounds identified in (1) synergistically improve the benefits of glucocorticoid treatment. This SBIR Phase II project falls within several aspects of the NIH ROADMAP FOR MEDICAL RESEARCH including the use of innovative phenotypic drug screening instrumentation to better understand the metabolic components and networks within tissues, creating new models to help predict the body's response to disease treatment. PUBLIC HEALTH RELEVANCE: Duchene muscular dystrophy (DMD) is a genetically inherited fatal skeletal muscle disease with few treatments currently available for slowing the loss of muscle strength. Myomics' high content drug screening technology is aimed at identifying new drug candidates to attenuate skeletal muscle loss and thereby increase muscle strength. While not a cure for the disease, these new drug therapies are aimed at enhancing quality and longevity of life of the DMD patient.