Drug Designing: Open Access
Open Access

Preclinical drug discovery with patient-specific engineered heart tissues

International Conference and Expo on Drug Discovery & Designing

August 11-13, 2015 Frankfurt, Germany

Tetsuro Wakatsuki

Posters-Accepted Abstracts: Drug Des

Abstract :

American healthcare system spends >$200 billion in cardiovascular treatment. Inter-individual variability in efficacy and toxicity
response is rather large for cardiovascular treatments. InvivoSciences has developed an in vitro disease model that recapitulates
individual patient’s cardiomyopathy in engineered heart tissues (EHTs) using the patient-derived cells. Automated cell culture and
novel cardiomyocyte-differentiation protocol improved the productivity and reproducibility for generating patient-specific disease
models for drug and diagnostics development.
The application of our technology to establish a patient-specific disease model for a rare disease, Muscular Dystrophy (MD), will
be discussed. While the exon skipping treatment could finally overcome skeletal muscle wasting of Duchenne muscular dystrophy
(DMD), it depends on skeletal muscle’s high regenerative capacity. Therefore, the limited regenerative capacity of cardiac muscle
encounters challenges for treating DMD heart failure, which was recognized only recently. Mass-produced micro-scale EHTs
from patient-derived cardiomyocytes using induced pluripotent stem cell technology recapitulate a patient-specific DMD heart
failure phenotype in vitro and screen compounds for drug discovery. A detection of slowly developing DMD cardiac phenotypes
in EHTs was required to comprehensively analyze their excitation-contraction-energy coupling (ECEC) by measuring their action
potential, calcium transient, cardiac contractility, and mitochondrial metabolism by a high-throughput assay device under various
stress conditions. Combining multi-scale (i.e., molecule to whole body) computational models of human physiology with the ECEC
analysis of EHTs will predict clinical outcomes (e.g., cardiotoxicity and efficacy) of a potential treatment at the preclinical stage. The
project will support discovery of disease mechanisms to identify potential targets for therapy.