SYS-CON MEDIA Authors: Roberto Medrano, Dmitriy Stepanov, Gilad Parann-Nissany, Sean Houghton, Glenn Rossman

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Sigma® Life Science Launching Genetically-Modified HepaRG™ Human Liver Cells Licensed from Biopredic for Cell-based ADME/Tox Assays

ST. LOUIS, Jan. 17, 2014 /PRNewswire/ -- Sigma-Aldrich Corporation (NASDAQ: SIAL) today announced that Sigma Life Science, its innovative biological products and services business, will be launching the genetically-modified HepaRG human liver cell line, licensed from Biopredic, for hepatotoxicity and drug metabolism assays. Currently undergoing beta-testing by multiple contract research and pharmaceutical organizations, the assays will be publicly available later in Q1 2014 in a plated, live-cell format to support translational research in industry and academia. Through this license agreement with BioPredic International, Sigma-Aldrich will also offer high-quality wild-type HepaRG liver cells and supporting media.

In drug discovery and development, unforeseen toxicity issues, particularly in the liver, remain a major cause of late-stage drug failures that account for billions of dollars of lost pharmaceutical R&D investments. This has recently prompted regulators and pharmaceutical companies to issue guidance and develop robust studies to predict liver toxicity. However, current assays using animals or in vitro techniques—such as utilizing small molecule inhibitors, RNAi, or less than desirable cell lines—introduce biological ambiguity, off-target effects or limit the extent of acquirable data.

To generate novel, precision assays for early prediction of hepatic liabilities, Sigma-Aldrich will apply its exclusive CompoZr® Zinc Finger Nuclease (ZFN) gene editing technology on the HepaRG human liver cells. Sigma-Aldrich plans to knock-out genes for critical xenobiotic sensors—such as PXR and CAR—and drug transporters—including BSEP, OATP1B1, and OATP1B3—that regulatory agencies have highlighted for possible analysis. The gene knock-out approach, only recently possible in human cells due to the advent of robust gene-editing tools such as CompoZr ZFNs, eliminates the ambiguities about a drug's interactions that would be introduced by conventional tools, such as small molecules or RNAi. Sigma-Aldrich will also knock-in fluorescence reporter tags to endogenous toxicity biomarkers, such as ALT and Cytochrome P450, to generate inexpensive, high-throughput live cell imaging or reporter-based assays that can reveal toxic drug effects and drug–drug interactions.

"Such precision assays currently do not exist. These gene-edited HepaRG cell-based assays represent a major improvement in the quality of data compared to the predominant way of studying liver drug metabolism and toxicity, which is through primary human hepatocytes recovered from donated cadavers. These primary cells suffer from sporadic availability, loss of in vivo functions, variable donor health, and genetic polymorphisms that can confound reproducible analyses," explained Paul Brooks, Ph.D, Global Market Manager at Sigma-Aldrich.

The HepaRG immortalized cell lines from BioPredic International are unique in that they mirror the endogenous human hepatocyte functionality and metabolism(1,2,3) providing a dependable supply of long-lifespan, isogenic cells that eliminate confounding sources of variation. Other immortalized liver cell lines exist, including Fa2N-4 and HepG2, but all of these cell lines lack important biological features, such as expression of the Cyp3A4 enzyme that metabolizes more than 50% of currently approved drugs.

The beta testing program for the genetically-modified HepaRG cell lines is currently open to CRO, pharmaceutical, and academic partners.

Sigma-Aldrich currently offers several gene-edited human cell lines for ADME/Tox assays, including Caco-2 human liver cell lines with efflux transporter gene knock-outs for clear analysis of potential drug–drug interactions.

"The broad vision for Sigma-Aldrich's ADME/Tox R&D is to exploit gene-editing in human cell lines to provide  novel, isogenic assays that resolve fundamental shortfalls in current ADME/Tox methodologies.  By doing so, we can resolve a major hurdle in translational research,leading to safer drugs and more sustainable drug development programs," said Sean Muthian, Ph.D., Director of Strategic Marketing at Sigma-Aldrich.

For more information, visit sigma.com/admetox.

(1) Kanebratt et al. (2008) Drug Metab Dispos 36,137-145
(2) Hart et al. (2010) Drug Metab Dispos 38, 988-994
(3) McGill et al. (2011) Hepatology 53, 974-982

Cautionary Statement: The foregoing release contains forward-looking statements that can be identified by terminology such as "will be publicly available," "early prediction", "precision" or similar expressions, or by expressed or implied discussions regarding potential future revenues from products derived there from. You should not place undue reliance on these statements. Such forward-looking statements reflect the current views of management regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that this or any other joint venture will assist the Company to achieve any particular levels of revenue in the future. In particular, management's expectations regarding this joint venture could be affected by, among other things, the Company's ability to obtain or maintain patent or other proprietary intellectual property protection; competition in general; government, industry and general public pricing pressures; the impact that the foregoing factors could have on the values attributed to the Company's assets and liabilities as recorded in its consolidated balance sheet, and other risks and factors referred to in Sigma-Aldrich's current Form 10-K on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Sigma-Aldrich is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About Sigma-Aldrich:  Sigma-Aldrich, a leading Life Science and High Technology company focused on enhancing human health and safety, manufactures and distributes more than 200,000 chemicals, biochemicals and other essential products to more than 1.4 million customers globally in research and applied labs as well as in industrial and commercial markets. With three distinct business units – Research, Applied and SAFC Commercial – Sigma-Aldrich is committed to enabling science to improve the quality of life. The Company operates in 38 countries, has more than 9,000 employees worldwide and had sales of $2.6 billion in 2012. For more information about Sigma-Aldrich, please visit its website at www.sigma-aldrich.com.

Sigma-Aldrich and Sigma are trademarks of Sigma-Aldrich Co. LLC registered in the US and other countries. CompoZr is a trademark of Sigma-Aldrich Co. LLC. HepaRG is a trademark of BioPredic International.

SOURCE Sigma-Aldrich Corporation

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