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Abstract
Grant Number: 1R43NS059098-01 Project Title: High Content Screening for Muscular Dystrophy
PI Information: Name Title VANDENBURGH, HERMAN H. herman_vandenburgh@brown.edu ASSOCIATE PROFESSOR Abstract: DESCRIPTION (provided by applicant): Myomics' drug screening technology to be developed in this Phase 1 SBIR project for Duchene muscular dystrophy (DMD) is based upon an in vitro skeletal muscle tissue force measurement technique for high content screening (HCS) of compounds to attenuate muscle weakness. Currently, there are few drugs besides Prednisone which are used clinically to slow muscle weakness in DMD patients. The drug screening technology, termed Patterned Micro-Post-Arrays (P-fPA), is comprised of bioengineered skeletal muscle tissue attached to micro-mechanical sensors in a ninety-six well format to quantitatively measure muscle contractile forces. Miniature BioArtificial Muscles (mBAMs) are three-dimensional (3-D) contractile tissues with organized striated skeletal muscle fibers which can generate directed force when electrically stimulated. Myomics' mBAM tissue/sensor composite is capable of repetitive nondestructive force measurements long term over several weeks. The sensors therefore provide physiological data regarding tissue function in response to long-term exposure to a drug. Such long term studies can determine cumulative effects of drugs on 3-D tissues which are not apparent in shorter term single cell or monolayer screening technologies. mBAMs have been successfully engineered to grow within the sensors and generate force using P-fPA prototypes. The purpose of this project is to expand these preliminary studies into reproducible quantitative muscle force measurements for up to 14 days on mBAMs bioengineered from skeletal myoblasts isolated from the mdx mouse, a genetic animal model of DMD (Dystrophic mBAMs, DmBAMs). Briefly, the project will (1) determine optimal DmBAM bioengineering in the micro-post geometry for measuring DmBAM resting and active tetanic contractile forces as well as myofiber formation; (2) determine the damaging effects of DmBAM eccentric contractions based on creatine kinase release, force generation, and muscle fiber morphology; and (3) test the ability of Prednisone to attenuate this damage response. These studies will validate the P-fPA technology for DMD and lay the ground work for HCS screening of commercially available banks of compounds capable of attenuating the damaging effects of muscle use in dystrophic muscle. With Myomics' P-fPA technology, the physiological measurement of force generation by mBAMs is not limited to any particular known biochemical pathway and the measurement of force will be the result of both positive and negative drug effects. Thus, the technology will not only screen compounds for positive muscle growth effects through known as well as unknown pathways, but will more rapidly eliminate target compounds with potential adverse side effects. This will lead to a greater chance of success in follow-up preclinical animal studies in the mdx mouse and subsequent testing in Duchene muscular dystrophy patients for epigenetic drugs which can improve the longevity and quality of life of patients with this devastating disease. 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 to be developed in this project 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.
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Institution: MYOMICS, INC. SLATER CENTER FOR BIOMEDICAL TECHNOLOGY PROVIDENCE, RI 029065117 Fiscal Year: 2007 Department: Project Start: 15-SEP-2007 Project End: 31-AUG-2008 ICD: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE IRG: ZRG1