Bioengineering Mature Human Pluripotent Stem Cell-Derived Cardiomyocytes for Predictive Drug-Induced Toxicity Testing - PROJECT SUMMARY
Nearly 90% of drugs under development fail to reach the market. Many of these failures occur due to
cardiotoxicity, usually when the candidate molecule induces cardiac arrhythmias. In a few notable cases, some
drugs pass pre-clinical screens and clinical trials, only to be removed from the market once toxic effects are
discovered in large patient populations. These failures represent a tremendous source of waste and constitute
a significant part of the ~$2 billion cost of bringing a single drug to market. Consequently, the FDA now mandates
that all drugs undergo in vitro cardiotoxicity testing before being tested in humans. This has led to a significant
and growing market for tools and technologies that enable earlier detection of toxic effects before exposure to
patients. However, current screening methods fall short of predicting how a drug will behave in the body; indeed
there is a pressing need for more predictive model systems. Human induced pluripotent stem cell-derived
cardiomyocytes (iPSC-CMs) are an attractive model for in vitro preclinical toxicity screening; they are relatively
easy to maintain, are derived from human tissue, and have the potential to reduce the need for animal
experimentation. However, at present, iPSC-CM based assays do not properly replicate the function of the
human heart. These cells exhibit phenotypes similar to that of fetal tissue and do not respond as expected to
drugs of known effect; in some cases, known bad-actor drugs fail to induce arrhythmias, while others only show
in vivo cardiotoxicity when exposed to supra-physiological doses of the drug in question. The drug discovery
industry and its regulators realize the potential of iPSC-CMs for early cardiotoxicity screening, but also
understand that—at present—there are significant limitations to their use in the drug development process. Thus,
it is clear that the production of mature cardiac tissues that accurately recapitulate in vivo drug responses
represents a significant opportunity for reducing cost and waste in drug development. NanoSurface Biomedical,
Inc., aims to develop an enhanced iPSC-CM cell line that has been optimized for highly predictive drug-induced
cardiotoxicity screening. We hypothesize that iPSC-CMs that give more predictive results in in vitro cardiotoxicity
detection can be made by combining nanoscale extracellular cues with biochemical and molecular biological
stimuli that drive their maturation. We will first focus on demonstrating that these enhanced iPSC-CMs can
correctly classify drugs that are currently improperly screened (Phase 1, Aim 1). After validation, we will generate
a stable cell line that encompasses the maturation factors determined in Phase 1 in preparation for scaling and
commercial production (Phase 2, Aim 1). Commercialization efforts will further be facilitated by characterizing
transcriptomic, structural, and functional phenotypes of the predictive cell line and in identifying a set of key
physiological metrics that will be used for in-line quality control (Phase 2, Aim 2). Last, we will validate and
generate data for market release with our research partners in the drug development industry and regulatory
bodies (Phase 2, Aim 3).
