NEW YORK—In August, researchers from TARA Biosystems Inc. and GlaxoSmithKline (GSK) published data demonstrating that TARA’s engineered heart-on-a-chip system replicated drug responses found in adult humans. The findings, published in the Journal of Toxicological Sciences, show that TARA’s 3D cardiac tissue platform can predict how human hearts will respond to a wide range of drugs.
Regulations mandate that new drugs undergo cardiac safety assessment before human testing, but predicting how human hearts will respond to potential drug toxicity has been difficult. Traditional in-vitro systems and animal models fail to fully capture the physiology of the human heart.
“We need the ability to assess cardiac risk early in the development of a new medicine. Almost half of all drug recalls are due to cardiac toxicity that was not picked up during early screens. These human cardiac liabilities can go undetected because historically it has been challenging to predict how human hearts will respond to potentially cardiotoxic drugs, despite rigorous testing in both animals and in-vitro systems throughout drug development. Traditional in-vitro systems and animal models do not translate well to humans, and human donor tissue availability is limited for in-vitro testing,” says Dr. Misti Ushio, co-founder and CEO of TARA Biosystems.
“Additionally, cardiovascular disease remains the number one cause of death worldwide. We need the ability to develop new medicines that will reach patients sooner. By having predictive models of cardiac disease, we should be able to develop better medicines that will have a high chance of working in patients,” she adds. “The Biowire II platform enables us to generate cardiac disease models which can then be used to discovery new therapies for cardiovascular disease.”
“There is great potential for immature human-induced pluripotent stem cell cardiomyocytes (iPSC-CMs) to bridge the human translation gap, but it’s been a challenge to train these cells to recapitulate pharmacology seen in mature human heart cells. This stems from the fact that existing experimental models use (iPSC-CMs), which lack relevant physiological hallmarks of adult human cardiac muscle and therefore fail to predict drug responses seen in the clinic,” Ushio tells DDNews.
TARA subjects iPSCs to a rigorous maturation process on the company’s patented Biowire II system, producing 3D human cardiac tissues called Cardiotype tissues. In a study published earlier this year in Cell, TARA scientific founders validated the ability of the Biowire II platform to create physiologically relevant human cardiac tissues.
“Unlike other organ-on-a-chip platforms, the Biowire II platform not only matures the tissues, but also directly measures the force with which these engineered tissues contract. The platform enables researchers to gather human-relevant functional data in the lab, providing a surrogate measure for how effectively the human heart pumps blood in the presence of potentially toxic drugs,” Ushio continues.
“The findings of this study published in the Journal of Toxicological Sciences show that our engineered heart-on-a-chip system can predict how human hearts will respond to a wide range of drugs. We worked with researchers from GlaxoSmithKline to select a panel of clinically utilized drugs and tested them in the Biowire II platform. These drugs were chosen to assess the predictivity of our Cardiotype.Fo contractility assay for preclinical drug screening in pharmaceutical R&D,” says Ushio.
The tissues responded to the cardiotherapeutic and cardiotoxic drugs as expected, replicating for the first time the human-like response to the drugs that other laboratory models failed to capture. The researchers also confirmed the findings at the molecular level, showing that the drugs were acting along the same molecular pathways seen in human heart tissue.
“The cardiac tissues generated in the study are the first to provide high-fidelity human drug responses to a variety of compounds acting along molecular pathways important to human heart function,” explains Ushio. “These results demonstrate that our tissues have the correct internal machinery to function as a human heart muscle surrogate, and underscores the potential for this model to become part of the cardiac risk assessment paradigm for evaluating the efficacy and safety of new therapies in preclinical development.
“In this paper we validated the Biowire II platform by analyzing compounds with known responses. We can now confidently apply our technology to assess emerging compounds in drug discovery and development. In addition to GSK, other major pharmaceutical and biotechnology companies have validated our engineered cardiac tissue platform as a tool to tackle complex and challenging cardiac questions.
“We are excited by these new opportunities and anticipate them to be fruitful collaborations and mutually beneficial undertakings,” she points out. “We are also expanding the application of our technology to the generation and characterization of disease models for heart failure drug discovery to identify new targets and test the efficacy of new medicines, in addition to their safety.”
TARA is working with more than 20 pharmaceutical and biotech companies to assess cardiac risk and investigate novel cardiac disease models for heart failure drug discovery.
“Today, TARA is working with pharmaceutical companies to generate translational human cardiac models to help shorten drug development time by getting more human relevant data sooner, improving the efficiency of bringing a drug from the lab to the clinic. Availability of these models will reduce costs, reduce animal usage, and increase the success of their drug development pipelines to deliver better drugs to the market. With the Biowire II platform, disease and patient-specific models can also be generated, enabling both precision medicine and discovery of new heart disease medicines. At TARA, we are proud to tackle cardiac safety in a meaningful way that will ultimately improve the quality of new medicines delivered to patients,” concludes Ushio.