Heart-on-a-chip technology predicts preclinical systolic and diastolic in vivo observations

Graphical abstract of "A Platform for Generation of Chamber-Specific Cardiac Tissues and Disease Modeling" DOI: 10.1016/j.cell.2018.11.042 @ Cell

TARA Biosystems, Inc. today reported in vivo and in vitro functional data from a study of 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 will be presented today at the American Heart Association's Scientific Sessions in Philadelphia. MYK-491 is MyoKardia, Inc.'s lead clinical-stage activator candidate 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.

"These results are exciting because they demonstrate how TARA's advanced biology can really make an impact on the translation of clinical compounds," said Michael P. Graziano, PhD, 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 presented 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 showing 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, typically requiring studies in large animals with advanced instrumentation to capture such complex, integrated functional effects preclinically. TARA's organ-on-a-chip platform may offer an in vitro alternative to collect such measurements in a human setting.

"In the study reported today at AHA, TARA's human heart-on-a-chip technology provided confirmatory preclinical evidence of what we have seen in our other preclinical and clinical studies: MYK-491 appears to increase systolic contractility without impacting diastolic relaxation," said Robert McDowell, PhD, chief scientific officer of MyoKardia. "This platform may serve as a valuable human translational model for cardiovascular drug discovery with its ability to capture the nuances of human heart contraction and relaxation mechanics."

The uses of human induced pluripotent stem cells (iPSCs) holds great promise as a foundation to bridge the human translation gap. However, experimental models, which rely on iPSCs alone lack relevant physiological hallmarks and drug responses seen in human heart muscle. TARA leverages the power of iPSCs and subjects them to a rigorous maturation process on its 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. The research also showed how the platform could be used to model different heart diseases by using iPSCs from patients. Additionally, findings published recently in the Journal of Toxicological Sciences, show TARA's 3D-cardiac tissue platform predicts responses to a wide range of drugs known to affect cardiac function in humans, something that has been a challenge in pre-clinical models until now.

A Platform for Generation of Chamber-Specific Cardiac Tissues and Disease Modeling

Zhao Y, Rafatian N, Feric NT, Cox BJ, Aschar-Sobbi R, Wang EY, Aggarwal P, Zhang B, Conant G, Ronaldson-Bouchard K, Pahnke A, Protze S, Lee JH, Davenport L, Jekic D, Wickeler A, Naguib HE, Keller GM, Vunjak-Novakovic G, Broeckel U, Backx PH, Radisic M

Cell (2019) Volume 176, Issue 4, Page 913-927

DOI: 10.1016/j.cell.2018.11.042

Engineered Cardiac Tissues Generated in the Biowire II: A Platform for Human-Based Drug Discovery

Feric NT, Pallotta I, Singh R, Bogdanowicz DR, Gustilo MM, Chaudhary KW, Willette RN, Chendrimada TP, Xu X, Graziano MP, Aschar-Sobbi R

Toxicological Sciences (2019) Volume 172, Issue 1, Pages 89–97

DOI: 10.1093/toxsci/kfz168

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