A model replacement?

Heart-on-a-Chip technology predicts preclinical systolic, diastolic in-vivo observations for cardiac drug candidate

January 12, 2020
Mel J. Yeates
NEW YORK— TARA Biosystems, Inc. has reported in-vivo and in-vitro functional data from a study of an investigational candidate, MYK-491, showing that TARA’s human iPSC-derived organ-on-a-chip technology can directly measure in-vivo cardiac performance. These data were presented at the American Heart Association’s Scientific Sessions in Philadelphia, in November.
“The Biowire II platform generates three-dimensional tissues from induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and subjects them to a biomimetic maturation process. The resulting tissues exhibit physiological properties similar to that of human cardiac muscle and respond to a wide range of drugs used to treat cardiac diseases. Unlike other organ-on-a-chip platforms, the Biowire II platform directly measures the force with which these engineered tissues contract,” Misti Ushio, co-founder and CEO of TARA Biosystems tells DDNews. “The platform enables drug development researchers to gather human relevant functional data very early in the discovery process, providing a surrogate measure for how effectively the human heart pumps blood. Importantly, this approach also decreases the use of animal testing.”
MYK-491 is MyoKardia, Inc.’s lead clinical-stage activator candidate. It is designed to increase the contractility of the heart (systolic function), with minimal or no effect on myocardial relaxation and compliance (diastolic function), by acting directly on the proteins in the heart muscle responsible for contraction.
When asked why MYK-491 was chosen for this testing, Ushio notes that “MYK-491 ... [acts] directly on the proteins in heart muscle responsible for contraction. Historically, costly and time-consuming animal studies have been required to assess these key parameters. Uniquely, TARA’s platform provides the ability to rapidly assess measures of cardiac relaxation in a human-relevant setting. Recent studies of MYK-491 have validated that TARA’s platform can capture the nuances of human heart contraction and relaxation mechanics.”
“These results are exciting because they demonstrate how TARA’s advanced biology can really make an impact on the translation of clinical compounds,” said Dr. Michael P. Graziano, chief scientific officer of TARA Biosystems. “Replicating complex physiology in systems that up to now could only be seen in animals positions our technology as a faster, cheaper and more human-relevant alternative to animal testing.”
In the study, the effects of MYK-491 were evaluated in instrumented canine models and TARA’s human cardiac organoid model. The results indicate agreement between the two models—both showed improvements in systolic elastance (force production), with negligible effects on diastolic function.
Both systolic and diastolic tension are dysregulated in patients with heart failure and, given their load dependency, systolic and diastolic mechanics have been difficult to measure in an in-vitro setting. It typically requires studies in large animals with advanced instrumentation to capture such complex, integrated functional effects. TARA’s organ-on-a-chip platform could offer an in-vitro alternative to collect such measurements in a human setting.
“TARA’s human heart-on-a-chip technology provided confirmatory preclinical evidence of what was found in the other preclinical and clinical studies: MYK-491 appears to increase systolic contractility without impacting diastolic relaxation,” adds Ushio. “The compound has been assessed in Phase 1a and Phase 1b clinical trials and is currently in Phase 2a clinical studies.”
The use of human induced pluripotent stem cells (iPSCs) holds great promise as a foundation to bridge the human translation gap. But experimental models, which rely on iPSCs alone, lack relevant physiological hallmarks and drug responses seen in human heart muscle. TARA subjects iPSCs to a rigorous maturation process on its Biowire II system, producing 3D human cardiac tissues called Cardiotype tissues.
In an article published earlier this year in Cell, TARA scientific founders validated the ability of the Biowire II platform to create physiologically relevant human cardiac tissues. The research also showed how the platform could be used to model different heart diseases by using iPSCs from patients. And findings published recently in the Journal of Toxicological Sciences show that TARA’s 3D-cardiac tissue platform predicts responses to a wide range of drugs known to affect cardiac function in humans, which has been a challenge in preclinical models until now.
“We are working with several pharmaceutical partners to demonstrate the translation of our heart-on-a-chip system for a variety of applications,” Ushio pointed out. “Our objective is to continue to expand the opportunity space in support of drug discovery and clinical development. For instance, we are creating models of human cardiac disease by employing iPSC-derived heart cell lines from patients, and gene edited lines containing disease causing mutations. We are also expanding the number of parameters we can use to access the effect of disease and emerging medicines designed to treat them.”
“This research demonstrates the ability of TARA’s model to provide translational data by replicating complex physiology rather than relying on animal models, ultimately providing evidence that this model could be a faster, cheaper and more human-relevant alternative to animal testing,” Ushio concludes. “We are also expanding our platform for generating skeletal muscle models.”
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