Medical College of Wisconsin, Sangamo BioSciences, Inc., Sigma-Aldrich Corporation, Open Monoclonal Technology, Inc., And INSERM Researchers Create First Targeted Knockout Rats Using Zinc Finger Nuclease Technology

Milwaukee, WI, Richmond, CA, St Louis, MO, Palo Alto, CA and Paris, July 23, 2009 – Scientists from The Medical College of Wisconsin in Milwaukee, Sangamo Biosciences, Inc., (NASDAQ: SGMO), Sigma-Aldrich Corporation (NASDAQ: SIAL), Open Monoclonal Technology, Inc. (OMT) and INSERM today announced the creation of the first genetically modified mammals developed using zinc finger nuclease (ZFN) technology.

In a paper published in the July 24, 2009 issue of Science, researchers describe the novel application of ZFNs to generate rats with permanent, heritable gene mutations, paving the way for the development of novel genetically modified animal models of human disease. ZFN technology will make the generation of such animals faster and will create new opportunities in species other than mice.

“Until now, rat geneticists lacked a viable technique for “knocking out,” or mutating, specific genes to understand their function,” said Howard Jacob, Ph.D. Director of the Human and Molecular Genetics Center at the Medical College of Wisconsin. “This study demonstrates that ZFN technology bypasses the current need to conduct cumbersome experiments involving nuclear transfer (cloning) or embryonic stem cells and allows rapid creation of new animal models.”

In the study published in Science titled “Knockout Rats via Embryo Microinjection of Zinc Finger Nucleases,” (Geurts, et al.) scientists used ZFNs to knock out an inserted reporter gene and two native rat genes without causing measurable effects on other genes. Importantly, offspring of the ZFN-mutated rats also carried the modifications, demonstrating the genetic changes were permanent and heritable. Together, these results demonstrate the ability to deliver engineered ZFNs into early-stage embryos and rapidly generate heritable, knockout mutations in a whole organism.

Rats are physiologically more similar to humans than are mice for many traits and are ideal subjects for modeling human diseases. Extensive genetic characterization has revealed that approximately 90 percent of the rat’s 25,000-30,000 estimated genes are analogous to those in humans and mice, and their larger size makes them a superior model for drug-evaluation studies using serial sampling. Generating rats with knockout mutations has been a major challenge, but the new technique will increase the rat’s usefulness in research pertaining to physiology, endocrinology, neurology, metabolism, parasitology, growth and development and cancer. Along with his colleagues, Dr. Jacob’s team hopes to use knockout rats to gain a better understanding of disease processes related to hypertension, heart disease, kidney failure and cancer.

ZFNs are engineered proteins that induce double strand breaks at specific sites in an organism’s DNA. Such double-strand breaks stimulate the cell’s natural DNA-repair pathways and can result in site-specific changes in the DNA sequence. Previously, ZFNs were used to knock out specific genes in fruit flies, worms, cultured human cells and zebrafish embryos and are now in human clinical trials for the treatment of HIV/AIDS. This is the first example of successful gene editing in mammalian embryos using this technology.

“Our ZFN technology is widely applicable across species,” stated Philip Gregory, D.Phil., Sangamo’s vice president of research. “Used in conjunction with standard laboratory techniques, ZFNs provide a powerful solution to the challenge of making gene knockouts in cells and in whole organisms. We believe that this technology will become the method of choice for genome engineering in cells, plants and transgenic animals.”

In the first commercial application of this technique, OMT, a private biotechnology company developing a new rat-based human antibody platform, used Sangamo’s ZFNs to knock out the gene encoding rat immunoglobulin M (IgM), an important gene for rat antibody production. Inactivation of rat IgM expression is the first step in generating rats that exclusively express human antibodies encoded by transgenic human immunoglobulin genes. “Creating a knockout rat was the biggest challenge OMT faced”, said Dr. Roland Buelow, CEO of OMT and a senior author of the paper. “Inactivation of endogenous rat antibody expression is essential for human antibody expression in genetically engineered animals. To solve this problem, we used ZFN technology in an application that has the potential to revolutionize genetic engineering of animals.”

“We have invested our time and resources to develop the CompoZr platform because we see enormous potential in a technology that can precisely manipulate the genome of living organisms,” said Dr. David Smoller, President of Sigma-Aldrich’s Research Biotech business unit. “We are proud to be part of the public-private collaboration developing the proof-of-concept for this technique, which we believe will become the standard for the creation of genetically engineered research animals.”

Sigma-Aldrich, the sole source of commercial zinc finger nucleases for the research community, markets Sangamo’s ZFN technology through its CompoZrTM line of products and services. To get more information, please visit http://www.compozrzfn.com/.

About Sigma-Aldrich: Sigma-Aldrich is a leading Life Science and High Technology company. Its biochemical and organic chemical products and kits are used in scientific and genomic research, biotechnology, pharmaceutical development, the diagnosis of disease and as key components in pharmaceutical and other high technology manufacturing. The Company has customers in life science companies, university and government institutions, hospitals, and in industry. Over one million scientists and technologists use its products. Sigma-Aldrich operates in 36 countries and has 8,000 employees providing excellent service worldwide. Sigma-Aldrich is committed to Accelerating Customer Success through innovation and Leadership in Life Science, High Technology and Service. For more information about Sigma-Aldrich, please visit its award-winning Web site at http://www.sigma-aldrich.com.

About Sangamo Biosciences, Inc.: Sangamo BioSciences, Inc. is focused on the research and development of novel DNA-binding proteins for therapeutic gene regulation and modification. The most advanced ZFP TherapeuticTM development program is currently in Phase 2 clinical trials for evaluation of safety and clinical effect in patients with diabetic neuropathy and ALS. Sangamo also has a Phase 1 clinical trial to evaluate safety and clinical effect of a ZFP Therapeutic for the treatment of HIV/AIDS. Other therapeutic development programs are focused on cancer, neuropathic pain, nerve regeneration, Parkinson’s disease and monogenic diseases. Sangamo’s core competencies enable the engineering of a class of DNA-binding proteins known as zinc finger DNA-binding proteins (ZFPs). By engineering ZFPs that recognize a specific DNA sequence Sangamo has created ZFP transcription factors (ZFP TFTM) that can control gene expression and, consequently, cell function. Sangamo also is developing sequence-specific ZFP Nucleases (ZFNTM) for gene modification. Sangamo has established strategic partnerships with companies in non-therapeutic applications of its technology including Dow AgroSciences, Sigma-Aldrich Corporation and several companies applying its ZFP technology to engineer cell lines for the production of protein pharmaceuticals. For more information about Sangamo, visit the company’s web site at www.sangamo.com.

About the Medical College of Wisconsin: The Medical College of Wisconsin in Milwaukee, www.mcw.edu, is a private, freestanding academic institution dedicated to leadership and excellence in advancing the prevention, diagnosis and treatment of disease and injury through education, discovery, patient care and community engagement. A major national research center and academic medical center, its faculty physicians and scientists direct or collaborate on more than 3,000 research studies, publish over 1,300 peer-reviewed scientific papers, and provide care in virtually every specialty of medicine to approximately 350,000 patients annually. For more information on our transgenic services offering, see http://www.hmgc.mcw.edu/platforms/Transgenic_Core_Facility/

About Open Monoclonal Technology, Inc.: Open Monoclonal Technology, Inc. (“OMT”) is a private biotechnology company developing a new, fully human monoclonal antibody platform based on transgenic rats. The rat is a widely used laboratory animal with a well characterized immune system, a nearly complete genome sequence, and established transgenesis and hybridoma technologies. OMT’s antibody platform is the result of an improved understanding of B-cell development and a novel approach to the inactivation of endogenous antibody expression. The antibody platform is available for all targets, has broad freedom to operate, and uses technology protected by patents. For more information about OMT, contact Roland Buelow at rbuelow@omtinc.net or visit http://www.omtinc.net

About INSERM UMR 643: The INSERM UMR 643 is a French public academic laboratory. Its scientific activity is centered in the analysis of immune responses and in immunointervention strategies in organ transplantation. The rat is an important immunological model, and Inserm routinely generates transgenic rats using DNA or lentiviral vector microinjection. The generation of transgenic rats also is open to the scientific community through an open facility. More information is available at www.ifr26.nantes.inserm.fr/ITERT/transgenese-rat.

Cautionary Statement: This release contains forward-looking statements relating to future performance, goals, strategic actions and initiatives and similar intentions and beliefs and other statements regarding Sigma-Aldrich’s and Sangamo’s expectations, goals, beliefs, intentions and the like, which involve assumptions regarding the Companies' operations and conditions in the markets the Companies serve. Actual results may differ materially from these forward-looking statements due to a number of factors. See the Companies’ SEC filings, and in particular, the risk factors described in their Annual Reports on Form 10-K and their most recent report on Form 10-Q. The Companies do not undertake any obligation to update these forward-looking statements.

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