Although heart failure is the leading cause of death in the U.S., therapeutic treatments remain suboptimal as the pharmaceutical industry has proven incapable of generating more predictive human-relevant preclinical models of the human heart that are amenable to high-throughput screening (HTS) assays. Thus, vast compound libraries remain virtually unexplored in an effective manner, hindering the speedy development of new therapeutic approaches to treat heart disease. Organos, Inc. proposes a solution to this problem in the commercial development of an in vitro miniaturized array of "Micro-Heart Muscle" (µHM) amenable to HTS. Organos' innovation is that our HTS capable assay is based on heart muscle contraction metrics, which to date has neither been achieved nor is attainable in two-dimensional (2D) platforms. A main focus of this proposal is to create an HTS assay, using µHMs that fit a 384 microplate form factor, amenable to use with pre-existing automation. In the µHM, elongated muscle fibers are formed from induced pluripotent stem cell-derived cardiomyocytes (hiPSC- CMs) in polymer templates that promote uniaxial alignment and contraction, robust sarcomere assembly, and physiologically relevant drug responsiveness. The µHM 384 HTS platform and assay will lead the front end of Organos' discovery pipeline and feed data into our computational and deep learning models for compound discovery, target identification, and repurposing. The Specific Aims focus first on the fabrication of the HTS µHM platform, microtissue characterization, and assay development, then on validation and its use in HTS to identify compounds that improve cardiac contractility. The main outcome will be a robust HTS assay employing human heart muscle suitable for use in large screening campaigns for de novo drug discovery.
Public Health Relevance Statement: Narrative This proposal miniaturizes an advanced "heart-on-a-chip' system to perform a first-in-kind high throughput screening for cardiac drug development. Success of this proposal would open the path to needed rapid discovery of cardioactive compounds for repurposing or de novo heart treatment applications.
Project Terms: Automation; Back; Dorsum; Belief; Biological Assay; Assay; Bioassay; Biologic Assays; Calcium; Cause of Death; Computing Methodologies; computational methodology; computational methods; computer based method; computer methods; computing method; Cycloparaffins; Cyclic Olefins; Cycloalkanes; Drug Industry; Pharmaceutic Industry; Pharmaceutical Industry; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Electrophysiology (science); Electrophysiology; Neurophysiology / Electrophysiology; electrophysiological; Goals; Heart; Heart Diseases; Cardiac Diseases; Cardiac Disorders; heart disorder; Heart failure; cardiac failure; Human; Modern Man; In Vitro; Lead; Pb element; heavy metal Pb; heavy metal lead; Libraries; Muscle Contraction; Muscle Cell Contraction; Muscular Contraction; Myocardium; cardiac muscle; heart muscle; Polymers; Productivity; Development and Research; R & D; R&D; research and development; Sarcomeres; Software; Computer software; Technology; Testing; Tissues; Body Tissues; Work; base; improved; Physiological; Physiologic; prognostic; Fostering; Licensing; Myotubes; Rhabdomyocyte; Skeletal Fiber; Skeletal Muscle Cell; Skeletal Muscle Fiber; Skeletal Myocytes; Muscle Fibers; Therapeutic; tool; Myocardial depression; cardiac dysfunction; heart dysfunction; Myocardial dysfunction; Complex; System; 3-D; 3D; three dimensional; 3-Dimensional; copolymer; success; Structure; novel; Negotiating; Negotiation; Mediation; Devices; response; assay development; drug development; High Throughput Assay; high throughput screening; miniaturize; monolayer; drug discovery; drug mechanism; µfluidic; Microfluidics; Feeds; Data; Preclinical Models; Pre-Clinical Model; Reproducibility; Tissue Model; Validation; Cardiac; Development; developmental; virtual; software systems; Outcome; innovation; innovate; innovative; drug testing; drug detection; two-dimensional; 2-dimensional; human disease; novel therapeutic intervention; new therapeutic approach; new therapeutic intervention; new therapeutic strategies; new therapy approaches; novel therapeutic approach; novel therapeutic strategies; novel therapy approach; drug candidate; screening; predictive tools; microphysiology system; microphysiologic model; microphysiologic platform; microphysiologic system; microphysiology model; microphysiology platform; medication safety; drug safety; pharmaceutical safety; in silico; deep learning model; deep learning based model; induced pluripotent stem cell derived cardiomyocytes; iPS cell derived cardiomyocytes; iPSC derived cardiomyocytes
