Tuesday March 3, 2020 – Keystone, Colorado. TARA Biosystems Inc. today reported data showcasing its Biowire™ II as a platform for heart failure drug discovery. Speaking at this year’s Keystone Heart Failure Symposium, “Charting a New Course for Heart Failure: From Discovery to Data,” TARA’s Chief Scientific Officer, Michael P. Graziano, presented data demonstrating the use of TARA’s 3D engineered cardiac tissues (ECTs) to generate novel disease models of human cardiac pathologies. In vitro, human-based disease models that faithfully mimic pathology seen in patients would greatly facilitate the development of novel therapeutics for heart failure. Employing human induced pluripotent stem cell cardiomyocytes (hiPSC-CMs), TARA has created disease models by two different methods: (1) generating ECTs via chronic drug exposure to known cardiotoxic agents and (2) generating ECTs from iPSC-CMs with mutations known to cause cardiac disease in humans.
In the first model, TARA tested the effects of chronic incubation of healthy ECTs with doxorubicin, a cancer chemotherapeutic and cardiotoxin known to effect cardiac contractility and electrophysiology. In the second model, ECTs were generated from a commercially available hiPSC-CMs harboring a mutation in cardiac myosin (MYH7-R403Q) known to cause hypertrophic cardiomyopathy (HCM), and a CRISPR edited isogenic line in which the R403Q mutation was corrected back to the normal state. In both models, functional differences were observed similar to those seen in both healthy subjects and patients. Cardiac tissues exposed to chronic doxorubicin demonstrated decreased active force of contraction and action potential profile changes. ECTs harboring the MYH7-R403Q mutation displayed a greater active force and altered contraction kinetics compared to both the isogenic control and the healthy control tissues. In both cases functional changes reflect those observed clinically.
These results demonstrate the utility of TARA’s platform to model human heart failure and other cardiac diseases. The ability to create or correct a disease-relevant phenotype demonstrates that ECTs developed on the Biowire™ II platform can enable phenotypic-based heart failure drug discovery and development.