When breakthroughs surface, there is no way of missing them, or continuing demeaning their importance and impact on the future of medical practice. This time, using the biotechnology company SanGamo’s SGMO zinc finger nuclease (ZFN) technology has, indeed, created the first genetically modified mammals. The breakthrough was the result of efforts by scientists from various institutions and firms, including The Medical College of Wisconsin in Milwaukee, Sangamo Biosciences, the firm that created the zink finger nuclease (ZFN) technology, Sigma-Aldrich Corporation (NASDAQ:SIAL), Open Monoclonal Technology, Inc. (OMT) and INSERM. Together, they announced the scientific breakthrough and, in the mean time, validated SanGamo’s technology.
In a paper published in the July 24, 2009 issue of Science, the researchers described the novel application of ZFNs to generate rats having permanent, heritable gene mutations. Yes, we mean it, permanent and heritable gene mutations. This breakthrough is expected to lead to the development of novel genetically modified animal models of human disease. ZFN technology is expected to generate such animals faster and create new opportunities in species other than mice.
In the study 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.
This outstanding successful experiment is considered a breakthrough as it is the first capable of knocking out, or mutating specific rat genes, which is important, as rats are physiologically more similar to humans than are mice for many traits and are ideal subjects for modeling human diseases. Approximately 90 percent of the rat's 25,000-30,000 estimated genes are analogous to those in humans and mice. Their larger size makes them a superior model for drug evaluation studies using serial sampling. Generating rats with knockout mutations, however, has been a major challenge. Howard Jacob, Ph.D. Director of the Human and Molecular Genetics Center at the Medical College of Wisconsin said, "Until now, rat geneticists lacked a viable technique for 'knocking out,' or mutating, specific genes to understand their function. This study demonstrates that SanGamo’s 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."
Dr. Jacob's team hopes to use knockout rats to gain a better understanding of disease proc-esses 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.
Philip Gregory, D.Phil., Sangamo's vice president of research stated, "Our ZFN technology is widely applicable across species. 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). This is 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. Dr. Roland Buelow, CEO of OMT and a senior author of the paper said that the biggest challenge the firm had faced was creating a knockout rat, which ZFN technology has solved. He believes that ZFN technology has the potential to revolutionize genetic engineering of animals."
Dr. David Smoller, President of Sigma-Aldrich's Research Biotech business unit said that the firm has invested its time and resources to develop the CompoZr platform because it sees enor-mous potential in a technology that can precisely manipulate the genome of living organisms.” Dr. Smoller continued, "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 CompoZr™ line of products and services. To get more information, please visit www.compozrzfn.com/.
Prohost Comments: The reason for our enthusiasm and willingness to invest in the biotechnology industry is based on our confidence that some biotech firms are capable of using the abundant information into creating breakthroughs that take the practice of medicine and aggriculture into the future. As a matter of fact, thanks to some biotech firms, we are beginning to see the future, today.
Sigma-Aldrich is a leading Life Science and High Technology company with biochemical and organic chemical products and kits that 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 custom-ers 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 38 countries and has 7,800 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 www.sigma-aldrich.com.
Sangamo Biosciences focuses on the research and development of novel DNA-binding proteins for thera-peutic gene regulation and modification. The most advanced ZFP Therapeutic™ development program is currently in Phase 2 clinical trials for evaluation of safety and clinical effect in patients with diabetic neuropa-thy and ALS. Sangamo also has a Phase 1 clinical trial to evaluate safety and clinical effect of a ZFP Thera-peutic for the treatment of HIV/AIDS. Other therapeutic development programs are focused on cancer, neu-ropathic pain, nerve regeneration, Parkinson's disease and monogenic diseases. Sangamo's core compe-tencies enable the engineering of a class of DNA-binding proteins known as zinc finger DNA-binding pro-teins (ZFPs). By engineering ZFPs that recognize a specific DNA sequence Sangamo has created ZFP transcription factors (ZFP TF(NYSE:TM)) that can control gene expression and, consequently, cell function. San-gamo also is developing sequence-specific ZFP Nucleases (ZFN(TM)) 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 engi-neer cell lines for the production of protein pharmaceuticals. For more information about Sangamo, visit the company's web site at sangamo.com.
The Medical College of Wisconsin in Milwaukee, mcw.edu, is a private, freestanding academic insti-tution dedicated to leadership and excellence in advancing the prevention, diagnosis and treatment of dis-ease 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 www.hmgc.mcw.edu/platforms/Transgenic_Co.../.
Open Monoclonal Technology ("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 devel-opment 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 firstname.lastname@example.org or visit www.omtinc.net.
NSERM 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 mi-croinjection. The generation of transgenic rats also is open to the scientific community through an open facil-ity. More information is available at ifr26.nantes.inserm.fr/ITERT/transgenese-rat.
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