Ellis R.J.,Endocrine Oncology Branch |
Ellis R.J.,University of Pennsylvania |
Wang Y.,Genetics Branch |
Stevenson H.,Genetics Branch |
And 11 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014
Context: Aberrant DNA methylation is known to be a major factor in oncogenesis and cancer progression, but effects of methylation in papillary thyroid cancer (PTC) are not well defined. Objective: The objective of the study was to identify altered methylation patterns, which may be associated with PTC disease behavior. Design: This study was a genome-wide methylation analysis of PTC. Setting: The study was conducted at the National Institutes of Health Clinical Center. Patients: PTC tissue from 51 patients were analyzed and compared with normal thyroid tissue from seven patients. Interventions: CpG methylation status was assessed using advanced genome-wide methylation bead chips. Outcome Measures: Altered methylation patterns in PTC were analyzed by stage, recurrence, histological subtype of tumor, and tumor genotype. Results: PTC is globally hypomethylated compared with normal thyroid with 2837 differentially methylated CpG sites. The follicular variant of PTC demonstrated less differential methylation with only 569 differentially methylated CpG sites. Tumors with mutations in BRAF, RET/PTC, and RAS demonstrated a 3.6-fold increase in the number of differentially methylated sites compared with wild-type tumors. The differentially methylated genes were associated with oncological pathways including cellular movement, growth, and proliferation. Conclusion: PTC is epigenetically distinct from the follicular variant of PTC and by gene mutation status (BRAF, RET/PTC, and RAS). Copyright © 2014 by the Endocrine Society.
News Article | October 26, 2016
For the first time, National Institutes of Health (NIH) researchers have demonstrated in mice that gene therapy may be the best method for correcting the single faulty gene that causes Niemann-Pick disease, type C1 (NPC1). The gene therapy involved inserting a functional copy of the NPC1 gene into mice with the disease; the treated animals were then found to have less severe NPC1 symptoms. The study, led by researchers at NIH's National Human Genome Research Institute (NHGRI) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, was published Oct. 26, 2016, in the journal Human Molecular Genetics. Niemann-Pick disease is a rare and fatal disorder of the central nervous system (the brain and spinal cord) that has no cure. The disease occurs when a faulty housekeeping gene fails to remove cell waste, like lipids and cholesterol. The accumulation of waste in the spleen, liver and brain causes progressive deterioration in the intellectual and motor functions. It also shortens patient's lives, as people with Niemann-Pick disease typically die in their teens. There are several types of Niemann-Pick disease; this study focused on mice that had been bred with a faulty NPC1 gene to model Niemann-Pick disease, type C1. The researchers' goal was to correct the faulty NPC1 gene in as many cells and organs as possible, with a strong focus on the brain. To do this, they used a non-disease-causing virus called the adeno-associated virus serotype 9 (AAV9) to transfer functioning NPC1 to the cells. The AAV9 containing a functioning NPC1 gene successfully crossed the blood-brain barrier, reaching cells in the brain and elsewhere. Once inside cells, the normal NPC1 gene was then able to make the functional NPC1 protein to correct the cell defects. With a single injection, mice showed improvements in motor coordination, weight gain and longevity compared to those without this gene therapy. The effect of gene therapy equaled that of a drug called VTS-270, which has been evaluated in preclinical and clinical studies at numerous academic labs. However, to be effective, the VTS-270 compound has to be given for the life of the mouse. The team is now investigating if a combination of the two therapies will improve results. "We're very encouraged by this preliminary work," said William J. Pavan, Ph.D., senior investigator in the NHGRI Genetic Disease Research Branch. "The gene therapy is treating the root of the problem, the defective gene." "Our work in NPC1 mice may help lead to human clinical trials and eventually FDA approval for gene therapy as a treatment for NPC1 disease," said Charles P. Venditti, M.D., Ph.D., senior investigator in the NHGRI Medical Genomics and Metabolic Genetics Branch. "For NPC1 patients, gene therapy could halt progression of the disease, improve the quality of their lives and, hopefully, increase the patient's life span." The researchers work on gene therapy for NPC1 also has the potential to treat genetic disorders with some similar features. These might include mucolipidosis IV, Batten disease and Danon disease, researchers wrote. The advanced open access article can be found at: http://bit. . National Human Genome Research Institute (NHGRI) is one of the 27 institutes and centers at the NIH, an agency of the Department of Health and Human Services. The NHGRI Division of Intramural Research develops and implements technology to understand, diagnose and treat genomic and genetic diseases. Additional information about NHGRI can be found at: http://www. . About the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): NICHD conducts and supports research in the United States and throughout the world on fetal, infant and child development; maternal, child and family health; reproductive biology and population issues; and medical rehabilitation. For more information, visit NICHD's website. National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 institutes and centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www. .
News Article | February 16, 2017
BASEL, Switzerland and WATERTOWN, Mass., Feb. 16, 2017 (GLOBE NEWSWIRE) -- Lonza Houston, Inc., a global leader in viral gene and cell therapy manufacturing, and Selecta Biosciences, Inc. (NASDAQ:SELB), a clinical-stage biopharmaceutical company focused on developing biologic therapies for rare and serious diseases that avoid unwanted immunogenicity, have entered into a strategic manufacturing agreement. Under the terms of the agreement, Lonza will produce an Anc80-AAV-based gene therapy product for Selecta’s proprietary program for the treatment of Methylmalonic Acidemia (MMA), a rare inborn error of metabolism, and may in the future produce other Anc80-based products for which Selecta holds exclusive options. This relationship will leverage Lonza’s expertise in the development of robust and industry-scale manufacturing platforms for viral-based products. Data shows that Anc80-AAV, an in silico-designed synthetic gene therapy vector, has the potential to provide superior gene expression levels in retina, liver, muscle, cochlea’s outer hair cells and other tissue targets in preclinical studies, as well as reduced cross-reactivity as compared to naturally occurring adeno-associated viral vectors (AAVs) that are currently in clinical development. “This agreement with Selecta Biosciences continues to demonstrate Lonza’s leadership position in the cell and gene therapy space,” said Andreas Weiler, Ph.D., Head of Emerging Technologies Business Unit for Lonza’s Pharma&Biotech segment. “Lonza will utilize our extensive cGMP manufacturing knowledge and world-class quality systems to help Selecta Biosciences develop promising novel therapeutics for patients impacted by MMA and other devastating diseases.” “We at Selecta are focused on combining novel and proprietary viral vectors with our immune tolerance Synthetic Vaccine Particles (SVP™) to enable the first non-immunogenic gene therapies, providing the potential for repeat dosing,” said Werner Cautreels, Ph.D., Selecta’s president, CEO and chairman. “We view Lonza – one of the industry’s largest contract manufacturers of biologics and a leading supplier in gene therapy – as an ideal partner. They already have invested in developing various expression technologies, and they share our excitement about Anc80. We look forward to working with them to bring the first Anc80-based program into the clinic as a potential treatment for patients afflicted with MMA.” MMA is an inborn error of metabolism that, according to the National Institutes of Health (NIH), affects an estimated one in 25,000 to 48,000 individuals globally. MMA patients are unable to process certain proteins and fats, leading to the accumulation of toxic metabolites. Symptoms start to develop in early childhood and, despite strict diet, patients suffer from a wide range of disease-related complications such as pancreatitis, strokes and chronic kidney failure. Selecta exclusively licensed Anc80 for MMA from Massachusetts Eye and Ear® (MEE) in May 2016. Under the license agreement, Selecta also has the exclusive option to develop gene therapies using Anc80 for additional pre-defined lysosomal storage, genetic muscular and genetic metabolic diseases. Selecta intends to combine Anc80 with recently discovered transgenes and Selecta’s SVP-Rapamycin to create a novel gene therapy candidate for MMA. This candidate is intended to a) enable the treatment of patients with and without pre-existing anti-AAV antibodies; b) prevent cellular immune responses that often reduce the expression levels of gene therapies; and c) provide the ability to administer repeat gene therapy doses to achieve sufficient levels of methylmalonyl-CoA mutase (MUT), the enzyme that MMA patients are lacking. To advance the MMA program, Selecta entered into a Collaborative Research and Development Agreement (CRADA) with MEE and the National Human Genome Research Institute, NIH, in 2016. Principal investigators in this CRADA initiative are Charles Venditti, MD, PhD, Senior Investigator and Head, Organic Acid Research Section, Medical Genomics and Metabolic Genetics Branch and Luk Vandenberghe, PhD, Director of the Grousbeck Gene Therapy Center at MEE and an Assistant Professor at Harvard Medical School. A physician-scientist specializing in the study of inborn errors of metabolism including MMA, Dr. Venditti and his group have published several studies showing the effectiveness of gene therapy as a treatment for MMA in mice. Dr. Vandenberghe from MEE is the inventor of Anc80. Lonza is one of the world’s leading and most-trusted suppliers to the pharmaceutical, biotech and specialty ingredients markets. It harnesses science and technology to create products that support safer and healthier living and that enhance the overall quality of life. Not only is Lonza a custom manufacturer and developer, the company also offers services and products ranging from active pharmaceutical ingredients to drinking water sanitizers, from nutritional and personal care ingredients to agricultural products, and from industrial preservatives to microbial control solutions that combat dangerous viruses, bacteria and other pathogens. Founded in 1897 in the Swiss Alps, Lonza today is a well-respected global company with approximately 40 major manufacturing and R&D facilities and more than 10,000 full-time employees worldwide. The company generated sales of CHF 4.13 billion in 2016 and is organized into two market-focused segments: Pharma&Biotech and Specialty Ingredients. Further information can be found at www.lonza.com. Selecta Biosciences, Inc. is a clinical-stage biopharmaceutical company focused on developing biologic therapies for rare and serious diseases that avoid the immune responses that compromise efficacy and lead to life-threatening complications. Selecta is applying its proprietary Synthetic Vaccine Particles (SVP™) to a range of therapeutic areas in which immunogenicity is a key challenge. SEL-212, the company’s lead candidate in Phase 2, is being developed to treat chronic refractory gout patients and reduce their debilitating symptoms, including flares and inflammatory arthritis. Further, Selecta’s two proprietary gene therapy product candidates have the unique potential to enable repeat administration, allowing for dose adjustment in patients and maintenance of therapeutic activity over time. The company is seeking to expand the use of its SVP platform in other areas, such as immuno-oncology, allergies, autoimmune diseases and vaccines. Selecta is based in Watertown, Massachusetts. For more information, please visit http://selectabio.com. Additional Lonza Information and Disclaimer Lonza Group Ltd has its headquarters in Basel, Switzerland, and is listed on the SIX Swiss Exchange. It has a secondary listing on the Singapore Exchange Securities Trading Limited (“SGX-ST”). Lonza Group Ltd is not subject to the SGX-ST’s continuing listing requirements but remains subject to Rules 217 and 751 of the SGX-ST Listing Manual. Certain matters discussed in this news release may constitute forward-looking statements. These statements are based on current expectations and estimates of Lonza Group Ltd, although Lonza Group Ltd can give no assurance that these expectations and estimates will be achieved. Investors are cautioned that all forward-looking statements involve risks and uncertainty and are qualified in their entirety. The actual results may differ materially in the future from the forward-looking statements included in this presentation due to various factors. Furthermore, except as otherwise required by law, Lonza Group Ltd disclaims any intention or obligation to update the statements contained in this release. Selecta Biosciences, Inc. Disclaimer Any statements in this press release about the future expectations, plans and prospects of Selecta Biosciences, Inc. (“the company”), including without limitation, statements regarding the development of its pipeline, the ability of the company’s SVP platform, including SVP-Rapamycin, to mitigate immune response and create better therapeutic outcomes, the potential treatment applications for products utilizing the SVP platform in areas such as gene therapy, immuno-oncology, allergies, autoimmune diseases and vaccines, whether the company’s proprietary gene therapy product candidates will enable repeat administration, allow for dose adjustment in patients or maintain therapeutic activity over time, the sufficiency of the company’s cash, cash equivalents, investments, and restricted cash and other statements containing the words “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “hypothesize,” “intend,” “may,” “plan,” “potential,” “predict,” “project,” “should,” “target,” “would,” and similar expressions, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including, but not limited to, the following: the uncertainties inherent in the initiation, completion and cost of clinical trials including their uncertain outcomes, the unproven approach of the company’s SVP technology, undesirable side effects of the company’s product candidates, its reliance on third parties to manufacture its product candidates and to conduct its clinical trials, the company’s inability to maintain its existing or future collaborations, licenses or contractual relationships, its inability to protect its proprietary technology and intellectual property, potential delays in regulatory approvals, the availability of funding sufficient for its foreseeable and unforeseeable operating expenses and capital expenditure requirements, substantial fluctuation in the price of its common stock, a significant portion of the company’s total outstanding shares have recently become eligible to be sold into the market, and other important factors discussed in the “Risk Factors” section of the company’s Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission, or SEC, on November 10, 2016, and in other filings that the company makes with the SEC. In addition, any forward-looking statements included in this press release represent the company’s views only as of the date of its publication and should not be relied upon as representing its views as of any subsequent date. The company specifically disclaims any obligation to update any forward-looking statements included in this press release.
Abaan O.D.,Genetics Branch |
Polley E.C.,U.S. National Cancer Institute |
Davis S.R.,Genetics Branch |
Zhu Y.J.,Genetics Branch |
And 11 more authors.
Cancer Research | Year: 2013
The NCI-60 cell lines are the most frequently studied human tumor cell lines in cancer research. This panel has generated the most extensive cancer pharmacology database worldwide. In addition, these cell lines have been intensely investigated, providing a unique platform for hypothesis-driven research focused on enhancing our understanding of tumor biology. Here, we report a comprehensive analysis of coding variants in the NCI-60 panel of cell lines identified by whole exome sequencing, providing a list of possible cancer specific variants for the community. Furthermore, we identify pharmacogenomic correlations between specific variants in genes such as TP53, BRAF, ERBBs, and ATAD5 and anticancer agents such as nutlin, vemurafenib, erlotinib, and bleomycin showing one of many ways the data could be used to validate and generate novel hypotheses for further investigation. As new cancer genes are identified through large-scale sequencing studies, the data presented here for the NCI-60 will be an invaluable resource for identifying cell lines with mutations in such genes for hypothesisdriven research. To enhance the utility of the data for the greater research community, the genomic variants are freely available in different formats and from multiple sources including the CellMiner and Ingenuity websites. © 2013 AACR.