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Predicting side effects before they happen

Human Blood Vessel-Chip successfully mimics and predicts drug-induced thrombosis that was unforeseen in animal trials

Predicting side effects before they happen
In non-thrombotic conditions, platelets (purple) and fibrin (blue) are spread out on the surface of endothelial cells in the Blood Vessel-Chip. Credit: Emulate, Inc.

By Lindsay Brownell

(BOSTON) — Less than one in ten of the thousands of drugs that enter clinical trials every year ever make it to patients, usually because of intolerable side effects that are not seen until the drugs are given to human test subjects. Now, a collaboration between Wyss Institute spin-out Emulate, Inc. and Janssen Pharmaceuticals has demonstrated that a human Blood Vessel-Chip developed with technology pioneered at the Wyss Institute can accurately model and predict a blood clotting side effect that caused an autoimmune disease drug to be pulled from clinical trials in 2002, even though this toxicity was never observed in pre-clinical animal testing. This approach could be used in future drug development efforts to identify and test new potential drugs quickly and more accurately, thus reducing the cost and time required to get a drug to the market successfully. The study is published in Clinical Pharmacology and Therapeutics.

This research provides an example of how Organ Chip technology can provide value to pharmaceutical and biotechnology companies, as the human Blood Vessel-Chip was able mimic human toxicities that animal models could not. This raises the possibility of someday using human Organ Chips for pre-clinical testing, particularly in diseases for which there are no effective animal model alternatives.

The drug used in the study, hu5c8, is a monoclonal antibody that binds to and blocks the activity of a protein called CD154, which is found on the surfaces of several types of cells and is known to be associated with the development of autoimmune disorders and cancer. What was not known before hu5c8 was tested in humans, however, is its tendency to cause blood clots, which was only discovered after three years of clinical trials that put patients’ lives at risk and cost the sponsoring company untold dollars. The collaboration between Emulate and Janssen provided a case study on which to test whether the human Blood Vessel-Chip, which consists of a plastic chip containing a channel that is lined with human endothelial cells and perfused with whole human blood, could mimic responses seen in human blood vessels in vivo.

Predicting side effects before they happen
Blood in the Blood Vessel-Chip treated with the thrombosis-inducing molecule soluble collagen formed a meshwork of complex fibrin-rich clots containing mostly red blood cells with altered stellate morphology (fibrin in blue and red blood cells in purple), mimicking the effects of soluble collagen in vivo. Credit: Emulate, Inc.

When hu5c8 was added to the human Blood Vessel-Chip, it recapitulated the occurrence of thrombosis and recreated its key features, such as endothelial cell activation, platelet adhesion, platelet aggregation, fibrin clot formation, and thrombin anti-thrombin (TAT) complexes. Additionally, the researchers were able to examine the interaction of hu5c8 with specific blood components, analyze new biomarkers of thrombosis risk, and evaluate a modified form of hu5c8 that did not appear to cause thrombosis – a possible second life for a compound previously relegated to the massive graveyard of failed drugs.

This new development emerged out of work first initiated at the Wyss Institute in collaboration with Janssen Pharmaceuticals before many of its Organ-Chip team members spun out with Emulate, Inc. in 2014, where they advanced this effort and brought it to completion. Read further details about the study on Emulate’s website here.

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