High Content Drug Screening with Cardiac Tissue

DESCRIPTION (provided by applicant): Myomics, Inc. has developed High Content Drug Screening (HCS) technology for in vitro testing of compounds which alter contractile forces generated by miniaturized tissue engineered organs (Myo-Force Assay SystemTM, MFA STM). Myomics' 3-D tissue/force sensor composite is capable of long term studies (1-4 weeks) and provides force as well as electrophysiological activity data in response to a drug or multiple drugs in a nondestructive, repetitive fashion. Such long term st udies can determine effects of drugs on tissues which may not be apparent in shorter term single biochemical High Throughput Screening (HTS) assays. Unlike cell-based HCS assays, MFASTM retains properties of the original contractile tissue, allowing for fo llow-up histological and biochemical correlation to tissue contractile force. Since the physiological measurement of force is assayed, the effects of drugs on contractile properties are the sum result on multiple second messenger pathways (both positive an d negative effects). The technology may thus be a better predictor of subsequent in vivo activities. In addition, since the screening method does not target any particular known second messenger pathway as in most HTS and HCS assays, new pathway targets ma y be identified. Myomics has successfully tissue engineered skeletal muscle myoblasts into miniaturized bioartificial muscles (mBAMs) in a prototype 96 well format, reproducibly measured both isotonic (resting) and active (electrically- induced) contractil e forces, and validated the assay with known anabolic and catabolic factors. This Phase 1 SBIR project will extend the MFASTM technology to neonatal rat cardiomyocyte mBAMs (cBAMs) for potential use in screening for compounds to treat heart diseases affect ing heart force contraction or electrophysiological activity. Methods will be developed for the reproducible tissue engineering of cBAMS in a 96 well format and measurement of force generation with the MFASTM. Follow-up electrophysiological, biochemical, a nd histological assays will be performed to determine the differentiation state of the tissue by measuring electrical coupling, contractile protein isoform content, cellular organization, cell number and size. Successful completion of this project will all ow Myomics to utilize an automated 96 well plate MFASTM in a SBIR Phase II project to screen chemical compounds bank for potential treatment of heart disorders such as pathological cardiac hypertrophy or cardiac arrhythmias. Heart failure is a major public health problem and number one cause of death in industrialized nations. About 550,000 new cases occur in each year in the United States, and heart failure is the underlying or contributing cause of ~285,000 deaths per year and the estimated direct and ind irect costs (i.e., health care expenditures and loss of productivity, respectively) of heart failure in 2006 are estimated to be more than 25 billion. Few drugs are currently available to treat these disorders and Myomics' high throughput drug screening te chnology will enable the identification of new drugs candidates to attenuate cardiac disorders.