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Madison, WI, United States

Hediger M.A.,University of Bern | Clemencon B.,University of Bern | Burrier R.E.,University of Bern | Burrier R.E.,Stemina Biomarker Discovery, inc. | Bruford E.A.,HUGO Gene Nomenclature Committee
Molecular Aspects of Medicine | Year: 2013

The field of transport biology has steadily grown over the past decade and is now recognized as playing an important role in manifestation and treatment of disease. The SLC (solute carrier) gene series has grown to now include 52 families and 395 transporter genes in the human genome. A list of these genes can be found at the HUGO Gene Nomenclature Committee (HGNC) website (see www.genenames.org/genefamilies/SLC). This special issue features mini-reviews for each of these SLC families written by the experts in each field. The existing online resource for solute carriers, the Bioparadigms SLC Tables (www.bioparadigms.org), has been updated and significantly extended with additional information and cross-links to other relevant databases, and the nomenclature used in this database has been validated and approved by the HGNC. In addition, the Bioparadigms SLC Tables functionality has been improved to allow easier access by the scientific community. This introduction includes: an overview of all known SLC and "non-SLC" transporter genes; a list of transporters of water soluble vitamins; a summary of recent progress in the structure determination of transporters (including GLUT1/SLC2A1); roles of transporters in human diseases and roles in drug approval and pharmaceutical perspectives. © 2012 Elsevier Ltd. All rights reserved. Source

Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 742.78K | Year: 2015

DESCRIPTION provided by applicant Identification of Biomarkers of Cardiotoxicity using Metabolomics of Human Pluripotent Stem Cell Derived Cardiomyocytes Project Summary Abstract Cardiac safety is one of the leading causes of compound attrition in the pharmaceutical industry and withdrawal of FDA approved drugs from the market The purpose of this proposal is to improve public health as well as alleviate the financial burden of compound attrition due to cardiotoxicity through development of an in vitro assay to predict a compoundandapos s cardiotoxicity potential To accomplish this Stemina Biomarker Discovery andquot Steminaandquot proposes to use metabolomics of human induced pluripotent stem cell derived cardiomyocytes hiPSC CMs exposed to known human cardiotoxic and non cardiotoxic compounds These technologies will be used to discover human endogenous metabolite biomarkers which predict general cardiotoxicity as well as the specific type of cardiotoxicity e g functional structural The use of metabolomics to measure small molecules secreted by hiPSC CMs in response to compound exposure is a novel approach for evaluating cardiotoxicity and may pave the way for a new generation of more accurate predictive toxicology screens using human cells Stemina already used such a paradigm to complete the Phase I SBIR Application R GM as well as developed predictive methods to assess developmental toxicity potential in undifferentiated pluripotent stem cells devTOX tm Steminaandapos s long term goal is to develop a human cell based high throughput cardiotoxicity screen as a valuable tool to pharmaceutical biotech and agrichemical companies during early development of therapeutics and chemicals In order to achieve this goal Stemina first proposes to develop an optimized and reproducible experimental platform to evaluate spent media collected from hiPSC CMs aim We will evaluate various sample preparation methods LC MS columns and conditions and perform robustness testing in order to establish the most reproducible measurement of the complete set of secreted metabolites or secretome in hiPSC CMs using our system In aim we will use the above platform to evaluate spent media from hiPSC CMs response to a training set of compounds consisting of functional structural general and non cardiotoxicants to establish a predictive metabolomic model Small molecules whose abundances vary dependent upon whether cells were treated with an inducer or non inducer of cardiotoxicity will serve as candidate biomarkers of cardiotoxicity The data acquired here will be used to establish a predictive metabolic signature indicative of general cardiotoxicity and specific type of cardiotoxicity e g functional structural Stemina will then test the performace of the predictive model s of biomarker signature s on a test set of compounds In aim Stemina will confirm the structural identity of the predictive metabolites and evaluate their biological significance as confirmed biomarkers Lastly in aim a targeted biomarker assay will be developed using targeted LC MS methods that measure the confirmed biomarkers Further the ability of our biomarkers to adequately predict cardiotoxicity will be tested through the use o a blind study comprised of compounds acquired from partnering companies Completion of these aims will enable the development of a commercial assay able to detect the validated biomarkers of cardiotoxicity similar to an existing test Stemina currently markets for developmental toxicity devTOX tm quickPredict Stemina will subsequently utilize this assay to market a service capable of predicting whether a compound will induce cardiotoxicity and serve pharmaceutical companies in preclinical screening trials Such a service provides the first human cell based screening assay for cardiotoxicity founded on cardiomyocyte metabolism PUBLIC HEALTH RELEVANCE Identification of Biomarkers of Cardiotoxicity using Metabolomics of Human Pluripotent Stem Cell Derived Cardiomyocytes Project Narrative Adverse effects of drugs to patients are the fourth leading cause of death in the United States Drug induced cardiotoxicity remains one of the most common adverse drug effects indicating the need for better predictions of cardiotoxicity prior to a new drug reaching the market Stemina Biomarker Discovery proposes to develop and commercialize an in vitro assay based on biomarkers of cardiotoxicity from induced pluripotent stem cell derived cardiomyocytes that will predict the cardiotoxicity potential of drug candidates in order to decrease drug induced cardiotoxicity in humans therefore greatly improving public health and safety

Wisconsin Alumni Research Foundation and Stemina Biomarker Discovery, inc. | Date: 2010-10-06

The invention provides methods and biomarkers for assessing cardiac metabolic response to pharmaceuticals, environmental agents, chemical compounds and biologic therapies. The invention provides methods for identifying cellular metabolites secreted by primary cardiomyocytes, cardiomyocyte precursor cells, clonal cardiomyocytes derived from adult human heart, immortalized cardiomyocytes, human embryonic stem cell (hESC)-derived cardiomyocytes, human induced pluripotent stem cell (iPS)-derived cardiomyocytes, or any cell displaying cardiomyocyte-specific markers in response to exposure to pharmaceuticals, environmental agents, chemical compounds and biologic therapies that are cardiotoxic. Cardiomyocyte-secreted cellular metabolites provide metabolic signatures of cardiotoxicity, and can be used to screen pharmaceutical agents, lead and candidate drug compounds, biologics, and other therapeutics for cardiotoxic effects.

The invention provides biomarker profiles of metabolites and methods for screening chemical compounds including pharmaceutical agents, lead and candidate drug compounds and other chemicals using human stem-like cells (hSLCs) or lineage-specific cells produced therefrom. The inventive methods are useful for testing toxicity, particularly developmental toxicity and detecting teratogenic effects of such chemical compounds. Specifically, a more predictive developmental toxicity model, based on an in vitro method that utilizes both hSLCs and metabolomics to discover biomarkers of developmental toxicity is disclosed.

This present invention provides rapid, reproducible, biomarker-based screening methods for the developmental toxicity testing of compounds. The methods are designed to identify the exposure level at which a test compound perturbs metabolism in a manner predictive of developmental toxicity. In particular, the perturbation of two metabolites, ornithine and cystine, is measured, wherein a ratio of the fold change in ornithine to the fold change in cystine of less than or equal to about 0.88 is indicative of the teratogenicity of a test compound.

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