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CDI, Roche Will Use hESC-Derived Cells To Screen Rx Candidates for Cardiotox

Cellular Dynamics International this week said that it will use its cell-based assays to screen certain Roche drug candidates for cardiotoxicity.
Under the terms of the agreement, Roche will supply CDI with two sets of 25 well-characterized kinase inhibitors to validate CDI’s current crop of toxicology products and services, a Roche official told CBA News this week. CDI will test those compounds using human cardiomyocytes derived from human embryonic stem cells.
Kyle Kolaja, director of discovery and investigative safety at Roche, also said that Roche will generate cellular toxicity data using both biochemical and high-content imaging, while CDI will generate electrophysiology data. 
Both Parker and Kolaja declined to discuss financial details of the agreement.
‘Evaluation Phase’
“This is a proof-of-concept collaboration,” Chris Kendrick-Parker, CDI’s vice president for business development, told CBA News. It will last until data on at least 25 compounds have been generated at the Roche Palo Alto site and at CDI.
According to Parker, generating sufficient data should take approximately four to five months. He said Roche may also want to use CDI’s platform as a standard screening process within its discovery and safety assessment groups.
Added Kolaja: “This is really an evaluation phase. However, if all goes well, I can see it being extended beyond cardiomyocytes to other cell types, such as bone marrow … to test other types of target organ toxicities. Also, we will look at this as something that can be integrated into safety pharmacology studies.”
Roche has been looking for companies to help it develop better in vitro tools for predicting toxicity, Kolaja said. “CDI is one of these technology companies that was spun out of an academic environment. They have a lot of intellectual capacity and patents that they have access to that make them a leader in stem cell technology.”
Based on that and on CDI’s ability to create fully differentiated cardiomyocytes from hESCs, Kolaja said that Roche saw this as a way to test whether this model can predict cardiotoxicity.
“The reason I really like it, beyond the basic toxicology aspect, is that CDI also has a lot of expertise in electrophysiology, patch-clamping, and the prediction of QTc prolongation,” he added.

“If all goes well, I can see it being extended beyond cardiomyocytes to other cell types, such as bone marrow.”

Kolaja said that he had been seeking a way to integrate technologies that detect changes in cardiac conduction with those that detect cardiotoxicity in a simple yet elegant model, and “this seemed like a great opportunity.”
CDI was founded in 2005 by James Thomson, Craig January, and Tim Kamp from the University of Wisconsin, Parker said. “It was built from a collaboration at UW looking at differentiated cardiomyocytes to study the effects of compounds and drugs,” he explained.
In addition, January developed the HEK cell line for hERG screening to detect long QT syndrome, which forms part of the basis for the company’s screening business. The company also performs GLP hERG screening for IND filings for pharmaceutical companies.
Although CDI has other pharmaceutical customers for its hESC-derived cardiomyocyte supply and assay services, “This is the company’s first agreement of this kind with Roche,” Parker said.  
As the company further developed these tools, it was seeking out collaborators within the pharmaceutical industry to determine how these cell types would work in terms of safety testing and understanding drug mechanisms, Parker said.
Through his discussions with Roche over the years, and through previous collaborations with Kolaja, this collaboration fit in strategically with what Roche and CDI were trying to accomplish, said Parker.
CDI has a sister company called Stem Cell Products. The firms share management and facilities and have 18,000 square feet of R&D space at the University of Wisconsin Madison Research Park.
CDI has 30 employees, said Parker. SCP is primarily focused on hematopoietic cell models and long-term therapeutics, so the companies produce cell types derived from the mesodermic lineage and the hematopoietic lineage. Parker mentioned that cell types originating from the mesodermic lineage include adipose tissue, cardiomyocytes, chondrocytes, skin, neurons, and hepatocytes.
“Our business model is to develop humanized, cell-based models for basic research and toxicology,” said Parker, adding that the key element is being able to provide humanized cellular models that can be produced in sufficient quantities to do drug screening.
“We have built up automated cell culture methods to be able to generate large numbers of these terminally differentiated cell types from stem cells,” Parker said. 
According to Kolaja, the use of humanized, cell-based models such as CDI’s hESC-derived cardiomyocytes plays into recent efforts by other organizations to reduce, refine, or replace the use of animals in different types of testing, including toxicity testing (see CBA News, 2/8/08 and 2/15/08).


“You are combining two endpoints for which you will always have to generate data, because you always want to understand QTc prolongation and you always want to understand target organ toxicity,” said Kolaja.
He added that from the perspective of having a human-based model that ultimately could be more predictive than what investigators are currently using, a humanized cell-based assay will hopefully identify molecules that can get through the screening process safely.
“So at the end of this screening step, the drug candidates that are ‘clean’ will have a much higher likelihood of progressing without safety issues, and less time and money will be invested in drugs that will ultimately fail,” he said.   

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