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Geron, CXR, Roslin to Offer ADME/TOX Hepatocytes Derived From Stem Cells

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In a move that it anticipates will reduce the preclinical failure of drugs due to toxicity, Geron announced late last week that it is collaborating with CXR Biosciences and the Roslin Institute to develop and commercialize human embryonic stem cell-derived hepatocytes for use in drug metabolism and toxicity screens.

The company hopes to be offering ADME/Tox assays based on the hepatocytes by 2005, according to Geron CFO David Greenwood. Neither Geron nor CXR were able to disclose financial details of the agreement, which was announced on May 20.

Human liver cells, or hepatocytes, are among the most important cell lines for cell-based screening, mainly metabolism and toxicity studies. Tom Shepherd, CEO of CXR, said that as much as 60 percent of human drug toxicity is caused by hepatocyte toxicity. Coupled with the fact that most human drug candidates fail at the clinical level due to toxicity concerns, hepatocyte response is crucial for drug companies to monitor.

Unfortunately, Shepherd said, hepatocytes are traditionally among the most challenging cell lines to work with.

“There are two types of hepatocytes commonly used: Animal and human,” he said. “Human hepatocytes are more clinically relevant, but there are not really that many sources around, so a constant supply is important.”

In addition, Shepherd noted, hepatocytes are notoriously difficult to transform with reporter genes that would make them express a desired receptor or other protein for cell-based screening. Furthermore, hepatocytes differentiate frequently, which can quickly skew data from lot to lot.

Geron and CXR are banking on the idea that a stem cell-derived hepatocyte “will be much more stable and available,” Shepherd said. “This has got the potential to greatly increase hepatocyte use, which will give [drug companies] a better prediction of what will happen in clinical trials.”

Greenwood agreed. “If we could provide a supply of hepatocytes, and a reproducible supply, it would be a tremendous lift as a tool in drug discovery.”

The Roslin Institute, probably most noted for leading the cloning of “Dolly” the sheep, is a Geron collaborator and has been for several years. Greenwood said that Geron has been funding work at the institute since 1999, and that approximately two dozen of the company’s employees are stationed at the Dundee, UK-based institute.

According to an official statement from Geron, Roslin brings its expertise in human embryonic stem cell culture and gene reporter assays to the table, and will produce the stem cell-derived hepatocytes with Geron funding. In addition, Greenwood added, the institute’s proximity to the third partner, CXR, makes the collaboration even easier.

Greenwood said that CXR is primarily a contract research organization that develops cell-based assays, mostly involving hepatocytes and ADME/Tox screening. “[CXR] has technology that they bring to this partnership, as well,” Greenwood said, noting that the final marketable product is actually a full assay platform.

Shepherd told Inside Bioassays that CXR was also in the process of working out a partnership with an instrumentation company for reading and analyzing assays, although he declined to disclose which company that was. “It’s much more of a genetic or genomic platform,” he said.

Geron, which bills itself as a biopharmaceutical company focused on developing and commercializing therapeutic and diagnostic products for cancer, has been busy working with cell-based assay companies to commercialize products based on in-house discoveries and using its stem-cell and telomerase technologies.

Earlier this month, Geron announced that it had signed a licensing agreement with American Type Culture Collection to create and distribute cell lines immortalized with human telomerase reverse transcriptase. The company said that the cell lines will be available to the research-use-only market.

“The telomerase enzyme technology allows a cell to divide many more times than it normally would,” Greenwood said. He added that it is useful for any cell line, and that the company had been selling the technology through Becton Dickinson. Geron has intellectual property rights to both the telomerase and stem cell technologies, according to Greenwood.

He also said that there are not yet any advanced customers for the cell lines because “we don’t even have a product yet.” However, he said that Geron and CXR have already had conversations with several large pharmaceutical companies, and that anticipation is very high.

He added that the company would make the cells available to the entire research community as soon as they were ready, and that Geron would not be hoarding the technology for its own research purposes.

In Other Hepatocyte News

Creating highly reproducible and reliable cell lines seems to be the hot topic in cell-based screening these days. Just a day after Geron’s announcement, MultiCell Technologies of Warwick, R.I., announced two public presentations about its immortalized hepatocytes for drug screening.

First, Andrew Parkinson, founder and CEO of XenoTech, the technology’s licensee, presented on the topic at Cambridge Healthtech Institute’s Cell-Based Assays for High-Throughput Screening conference in Philadelphia on May 18 (see related story in this issue: Relevance, Reproduciblity, Reliability ...). In addition, MultiCell discussed the cell lines at its exhibit at the 3rd International BioExpo Japan, held May 19-21 in Tokyo.

According to an official company statement, MultiCell is developing cell-based toxological and drug screening assays, as well as biologics for diagnostic and therapeutic applications. In addition, MultiCell’s subsidiary Xenogenics is developing a synthetic liver device that is intended to “operate optimally” with the immortalized hepatocytes.

Shepherd told Inside Bioassays that the Geron and CXR approach seeks to solve the same problem — hepatocyte supply, or lack thereof — in a different way. “Although we’ve been trying to create reliable immortalized hepatocytes for several years, the idea of getting a phenotype similar to liver cells is very difficult,” he said. “Once hepatocytes are totally differentiated, it’s difficult to maintain the phenotype.”

“It’s not impossible, but we think that using embryonic stem cells, which are still flexible and plastic, it is easier to create cell lines that are closer to human liver cells,” Shepherd said. He also noted that the Geron/CXR hepatocytes would not be immortal, although they may have a longer lifespan than normal.

Calls to MultiCell representatives had not been returned when this publication went to press.

—BB

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