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News Article | May 18, 2017
Site: www.businesswire.com

ST. LOUIS--(BUSINESS WIRE)--Seventh Wave Laboratories, a consulting-based contract research organization that assesses the safety and efficacy of pharmaceutical products and medical devices, has announced an exclusive collaboration with Yecuris Corporation, a global leader in the development and use of humanized models in drug development research. The partnership enables the most predictive approach available to study new human liver disease therapies. Seventh Wave will now be the exclusive provider of services related to hepatitis B virus and C virus pharmacology studies using the Yecuris liver humanized FRG® KO model. Seventh Wave also will offer toxicology, metabolism and other pharmacology services using Yecuris models. Yecuris’ models are highly repopulated with human liver cells, making them an ideal candidate for efficacy studies of human liver pathogens. “Hundreds of millions of people are infected with hepatitis, and nearly one million die each year; there is a real need for a better way to evaluate new therapies,” said John Sagartz, PhD, DVM, president, CEO and founder of Seventh Wave Laboratories. “Yecuris’ models are top-tier humanized models for specific pharmacology evaluations that will allow us to study new human liver disease therapies. We are excited about the possibilities.” The two companies have been validating viremic and gene expression models for more than a year. “This agreement allows Seventh Wave access to our technology, and provides our clients access to a lab where they can have high-quality studies performed using our models,” said John Bial, CEO of Yecuris Corporation. Both Sagartz and Bial are confident this partnership will help researchers garner specialty data and expedite compound testing, ultimately benefiting people suffering from liver disease. About Seventh Wave Laboratories Seventh Wave Laboratories is a consulting-based contract research laboratory located in Maryland Heights, Mo., that provides integrated services for discovery and preclinical drug development. By integrating PK/ADME, bioanalysis, toxicology and pathology, the company provides local, national and international clients a multidisciplinary environment that accelerates their program and goals with focused strategy and execution. For more information, visit www.7thwavelabs.com or call 314.628.1123. About Yecuris Corporation Yecuris Corporation is a biotechnology company based in Portland, Oregon, that develops xenograft technologies to support primary human cell and organ engraftment for use in drug discovery, toxicology, infectious disease and cell therapy applications. Visit Yecuris' website: www.yecuris.com.


Duncan A.W.,Oregon Health And Science University | Duncan A.W.,McGowan Institute for Regenerative Medicine | Hanlon Newell A.E.,Oregon Health And Science University | Smith L.,Oregon Health And Science University | And 6 more authors.
Gastroenterology | Year: 2012

Murine hepatocytes become polyploid and then undergo ploidy reversal and become aneuploid in a dynamic process called the ploidy conveyor. Although polyploidization occurs in some types of human cells, the degree of aneuploidy in human hepatocytes is not known. We isolated hepatocytes derived from healthy human liver samples and determined chromosome number and identity using traditional karyotyping and fluorescence in situ hybridization. Similar to murine hepatocytes, human hepatocytes are highly aneuploid. Moreover, imaging studies revealed multipolar spindles and chromosome segregation defects in dividing human hepatocytes. Aneuploidy therefore does not necessarily predispose liver cells to transformation but might promote genetic diversity among hepatocytes. © 2012 AGA Institute.


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 212.37K | Year: 2011

DESCRIPTION (provided by applicant): Translational research in the field of liver disease has been limited by a shortage of large animal models, which in turn has limited development of new therapies for metabolic liver disorders, acute liver failure, chronic (cirrhotic) liver disease, an hepatocellular carcinoma. While new transgenic and knockout rodent models of liver disease have facilitated basic research, the development of bioengineered large animal models of liver disease has been problematic. To address the shortage of large animal models, we have utilized a novel strategy combining gene targeting by recombinant adeno-associated virus DJ serotype (rAAVdj) and somatic cell nuclear transfer (SCNT) for the production of bioengineered pigs. Our prototypemodel is hereditary tyrosinemia type 1 (HT1) accomplished by knocking out the gene coding for fumarylacetoacetate hydrolase (FAH) in pigs. In humans, FAH deficiency is associated with a unique phenotype, which includes metabolic derangement (tyrosinemia),acute liver failure, cirrhosis, and hepatocellular carcinoma (HCC). In mice, FAH deficiency combined with immune modulation has been used to produce mice with humanized livers (Azuma 2007 Nature Biotechnology; Bissig 2010 J Clinical Investigation). TheseFAH deficient mice serve as in vivo bioreactors for the robust expansion of normal human hepatocytes. We postulate that scale up of the FAH deficient platform to pigs is possible, and that FAH deficient pigs will also serve as surrogate hosts for much larger scale in vivo expansion of normal human hepatocytes. An abundant supply of human hepatocytes is needed for applications including toxicity testing of new drugs, human hepatocyte transplantation, and cell- based liver support devices such as the bioartificial liver. With regard to commercialization of this novel technology, we have already produced Fah-null heterozygote female pigs by rAAVdj and SCNT methodology. This phase 1 STTR (R41) application will establish a herd of FAH-deficient pigs and characterize the phenotype of Fah-null homozygote pigs. In future phase 2 studies, FAH-deficient pigs will be evaluated as in vivo bioreactors for the large-scale production of human hepatocytes. We expect that the FAH-deficient pig will serve as a valuable resource for the development of novel therapeutic modalities and to facilitate translational research in the field o liver disease. Furthermore, the rAAVdj and SCNT methodology may be utilized to produce other bioengineered large animal models of human disease.PUBLIC HEALTH RELEVANCE: The goal of the current research program is to develop a bioengineered pig with the metabolic disorder of human hereditary tyrosinemia type 1 (HT1). Phase 1 studies are designed to establish a herd of HT1 pigs and characterize the phenotype of these pigs. Phase 2 studies will determine if HT1 pigs can serve as in vivo bioreactors for large scale production of human hepatocytes. There are many therapeutic applications for normal human hepatocytes such as a cell-source in a bioartificial liver or for hepatocyte transplantation in humans, or industrial applications for safety and toxicity screening, or for use by pharmaceutical companies in the drug discovery process. Thus the demand for these new pigs is worthy of commercialization.


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase II | Award Amount: 773.67K | Year: 2011

DESCRIPTION (provided by applicant): The FDA requires the use of human hepatocytes for preclinical drug testing by pharmaceutical researchers, but unfortunately the supply of these cells is severely limited. Currently, cadaveric donors and surgical liver resection specimens are currently the only available source of human hepatocytes. These samples are very scarce and often yield cells of poor quality unsuitable for research. We have developed technology to massively expand fully functional primary human hepatocytes by serial transplantation in immune deficient FRGN mice in vivo. Hepatocytes isolated from these animals are highly viable and functional. Cell farming in FRGN mice allows the production of an unlimited supply of human hepatocytes for research in toxicology, drug metabolism, infectious disease, and cancer biology. The aims of this application are to optimize the isolation and storage of farmed hepatocytes and to fully validate their utility in comparison to the currently available cells. Once fully validated, these cells are going to be valuable in the commercial market. PUBLIC HEALTH RELEVANCE: The successful implementation of human hepatocyte farming technology will significantly impact human health by providing this vital resource for drug development at a higher quality and lower cost than is currently available.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 230.67K | Year: 2012

DESCRIPTION (provided by applicant): Chimeric mice with highly humanized livers have multiple potential applications in research and preclinical drug development both in the academic and commercial settings [1]. The applications include studies of human infectious diseases (hepatitis B and B, malaria etc.), drug metabolism and pharmacokinetics, drug-drug interactions, toxicology and gene therapy among others. In the current human chimeric liver models up to 90% of hepatocytes are of human origin and displayall the typical functions of mature human cells. Our company uses immune deficient fumarylacetoacetate hydrolase (Fah) knockout mice[2], bearing additional mutations in Rag2 and the interleukin common gamma chain receptor (Il2rg) designated as FRGN to generate such chimeric animals. Human hepatocytes from commercial vendors are transplanted into the animals and over time the human hepatocytes replace the mouse cells generating chimeric animals with livers that constitute 90% human cells. Currently, hepatocytes are the only human cell type present in FRGN chimeric livers and this represents a limitation for some applications of the model. Specifically, hematopoietic cell types are known to contribute significantly to liver biology, including pathobiology. Inflammation is present in many settings, particularly in liver infections, but also chemical injuries. Furthermore, the liver macrophages (Kupffer cells) are important players in liver toxicology. All of the hematopoietic cells in the current generation ofchimeric FRGN mice are of murine origin and they are completely deficient in T- and B-cells rendering the in sufficient for the afore mentioned studies. Chimeric mice bearing significant percentages of all human hematopoietic cells can be readily generated by transplantation of human cord blood into immune deficient mice, including Rag2/Il2rg/Nod mice. In this application we propose to optimize a protocol that permits the efficient generation of double- chimeric FRGN mice, with high levels of human hematopoiesis as well as high percentages of liver repopulation. Aim 1: To optimize a transplant protocol in FRGN mice which reproducibly yields gt70% human chimerism in both the liver and blood. 1a) Different time points for transplantation and different protocols or conditioning by irradiation will be compared using a single human hepatocyte donor. 2a) the two best protocols will be applied to 3 additional hepatocyte donors validate and further optimize the procedure. PUBLIC HEALTH RELEVANCE: Drug metabolism is phenotypically specific and can vary significantly between individuals of the same species and the variance between individuals can be attributed to genetic differences in the expression and activity of liver enzymes responsible for the metabolismof the drugs as well as significant contributions by the immune system in response to the metabolites produced by the liver. Yecuris Corporation has developed an in vivo genetic selection system (the FRG KO mouse) that permits extensive humanization of murine liver by transplanted human hepatocytes. With the addition of a humanized hematopoietic system in conjunction with the humanized liver, the new dual chimeric model could revolutionize development and screening of therapeutics in addition to providingmodels for studying hepatic infectious diseases.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: HEALTH.2013.2.1.1-1 | Award Amount: 16.16M | Year: 2013

Recently intense research identified around 4,000 single nucleotide polymorphisms (SNPs) associated with human age related diseases such as metabolic disorders. Despite their highly significant association to pathology, the functional role of these genetic variants is, in most cases, yet to be elucidated. The evolutionary distance of most animal models from humans represents a major limitation for the functional validation of these SNPs. To overcome these difficulties, HUMAN will generate mouse models carrying human hepatocytes or pancreatic cells from either primary cells (hepatocytes) or induced pluripotent stem cells (iPSCs). This innovative approach offers the unique possibility of studying function of genetic risk variants associated with metabolic diseases in an integrated living system (the mouse body), but within human-derived organs, i.e. liver and pancreas. iPSCs used to generate hepatocytes and cells will derive from extreme phenotypes, i.e. patients affected by severe metabolic diseases such as type 2 diabetes (T2D) or subjects selected for exceptional healthy longevity (subjects over 105 years and offspring of nonagenarian sibships) all fully clinically and metabolically characterised and genotyped; they will be selected according to the best combination of risk and protective alleles. We will test the effect of different nutritional regimes (e.g. high fat diet, caloric restriction), to disentangle the complex molecular mechanisms and circuitry across organs (e.g. hypothalamus-liver axis) which lead to pathology. HUMAN associates a core of outstanding basic research institutions to leading European biotech SMEs, and has the capability to produce at least 500 humanised mice. HUMAN will generate iPSCs biobanks and comprehensively manage all associated information. HUMAN is uniquely situated to drive innovation towards a better knowledge of the genetic basis of human metabolic diseases, thereby contributing to healthier aging of European citizens.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 243.21K | Year: 2014

DESCRIPTION (provided by applicant): Yecuris has developed an in vivo genetic selection system (the FRG KO mouse) that permits extensive humanization of murine liver by transplantation with human hepatocytes. This model has many potential commercial applications in drug development and testing, both in the in vivo and in vitro markets, .The mouse, however, is a small rodent and therefore the number of human hepatocytes that can be obtained for in vitro studies is limited to 80-150 million hepatocytes/animal. A larger animal that could be similarly repopulated would provide significant cost savings and economy of scale. Furthermore, the rat is the animal model of choice in many preclinical applications, particularly toxicology. For these reasons, we decided to generate an FRG KO rat, with mutations completely analogous to those in the FRG KO mouse: Fumary lacetoacetate hydrolase (Fah), Rag2 and common gamma chain of the interleukin receptor (Il2rg). Using TALEN and other gene editing technologies, st


Described herein are rats with a hepatic deficiency comprising decreased function, activity, or expression of an enzyme in the tyrosine catabolic pathway (such as fumarylacetoacetate hydrolase), and methods of using the same for in vivo engraftment and expansion of heterologous hepatocytes, such as human hepatocytes, analysis of human liver disease, and analysis of xenobiotics. Also disclosed is the use of immunodeficient rats for the engraftment and expansion of heterologous hepatocytes.


Described herein are rats with a hepatic deficiency comprising decreased function, activity, or expression of an enzyme in the tyrosine catabolic pathway (such as fumarylacetoacetate hydrolase), and methods of using the same for in vivo engraftment and expansion of heterologous hepatocytes, such as human hepatocytes, analysis of human liver disease, and analysis of xenobiotics. Also disclosed is the use of immunodeficient rats for the engraftment and expansion of heterologous hepatocytes.


Frg

Trademark
Yecuris Corporation | Date: 2012-08-27

Live laboratory and experimental animals; live mice, rats and pigs for scientific, laboratory or medical research.

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