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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.


Patent
Stemina Biomarker Discovery, inc. | Date: 2014-07-03

Methods for identifying metabolic signatures in blood plasma which are unique to autism are described herein. Samples are analyzed using multiple chromatographic-mass spectrometry-based techniques to orthogonally measure a broad range of small molecular weight metabolites differentially produced in autistic patient samples versus non-autistic control samples. These individual metabolites or a panel of such metabolites serve as metabolic signatures of autism. Such metabolic signatures are used in diagnostic methods to accurately identify individuals with autism spectrum disorder (ASD).


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.


Grant
Agency: NSF | Branch: Standard Grant | Program: | Phase: | Award Amount: 1.10M | Year: 2011

This Small Business Innovation Research (SBIR) Phase II project will fund a continuation of breakthrough research, development and commercialization of an in vitro assay to help prevent birth defects. This innovative product is driven by a need to create a test for human developmental toxicity that is more accurate than current tests that use animals. False negative results from these animal assays have lead to unexpected cases of birth defects, such as observed with Thalidomide. This assay, performed on human embryonic stem cells, is more predictive of developmental toxicity than animal models (80% vs 60%) and unlike animal models, provides data about specific human biochemical pathways that are affected. This will fund research to 1) identify biomarkers of developmental toxicity present in three different human cell lines, 2) optimize automation systems, 3) create a web-based interface to be used by customers, 4) standardize and create quality control procedures and 5) take the initial steps required for validation of the assay by the European Centre for the Validation of Alternative Methods (ECVAM). Upon validation, the test will be required in Europe for assessing developmental toxicity of newly developed pharmaceuticals and may be further used for testing of environmental chemicals as well.

The broader impacts of this research include 1) a global reduction in drug and chemical induced human birth defects 2) significant cost savings (up to $70 million per drug) for pharmaceutical companies allowing greater confidence in drug candidate selection and 3) a major global reduction in animal testing.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 146.67K | Year: 2012

DESCRIPTION (provided by applicant): Cardiotoxicity, as a result of adverse drug effects, is a serious problem that has yet to be effectively screened prior to patient exposure. 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 alleviate the financial burden of compound attrition due to cardiotoxicity, but more importantly, to improve public health through the development of an in vitro assay to predict a drug's ability to induce cardiotoxicity. Stemina Biomarker Discovery ( Stemina ) proposes to do so through the use of metabolomics on treated cardiomyocytes derived from human embryonic stem (hES) and human induced pluripotent stem (hiPS) cells. These technologies will be used to discover human endogenous small molecule biomarkers which predict cardiotoxicity, with an emphasis on cardiomyopathy. The use of metabolomics to measure small molecules secreted by human cardiomyocytes in response to drugs is a novel approach and may pave the way for a new generation of more accurate predictive toxicology screens. Stemina has already used such a paradigm to develop predictive methods to assess development toxicology in stem cells.Stemina's long-term goal is to fully develop this humanized, high throughput cardiotoxicity screen so that it would be a valuable tool to pharmaceutical and biotech companies during preclinical development of therapeutics. In order to achieve this long term goal, Stemina is first proposing to establish an experimental platform for each cardiomyocyte culture system (Aim 1). In Aim 2, we will use these systems to develop a dose response curve for each of the 24 compounds (16 cardiotoxic and 10 non-cardiotoxic) as a training set to establish a predictive metabolomic model. These dose response curves will be used to determine 3 concentrations for drug treatment to be utilized in Aim 3. Stemina will then establish a specific metabolic signature of candidate humanbiomarkers of drug-induced cardiotoxicity (Aim 3). To do so, human pluripotent stem (hPS) cell-derived cardiomyocytes will be treated with well-established known inducers and non-inducers of cardiotoxiciy. The spent medium from treated cells will be analyzed with mass spectrometry in order to study the secreted metabolites, or secretome, of these cells. 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. In future studies, these candidate biomarkers will be validated through the use of specialized mass spectrometry techniques. Lastly, the ability of these biomarkers to adequately predict cardiotoxicity will be tested through theuse of a blind study. Completion of these aims will encourage further discussions with partnering companies in order to develop a kit that can detect the validated biomarkers of cardiotoxicity. Stemina will then utilize this kit to market a service to predict whether or not a compound will induce cardiotoxicity that will serve pharmaceutical companies in pre-clinical screening trials. Such a service will provide the first humanized screening assay for cardiotoxicity based on cardiomyocyte metabolism and will likely improve public health. PUBLIC HEALTH RELEVANCE: Adverse effects of drugs to patients are the fourth leading cause of death in the United States; one such an adverse effect is drug-induced cardiotoxicity, illustrating a need for a better predictive assay for cardiotoxicity. Stemina Biomarker Discovery proposes to develop biomarkers of cardiotoxicity that would drive a service model to predict the cardiotoxicity-potential of drug candidates in order to prevent cardiotoxicity in patients. Sucha product will greatly improve public health.


Grant
Agency: National Science Foundation | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 500.00K | Year: 2011

This Small Business Innovation Research (SBIR) Phase II project will fund a continuation of breakthrough research, development and commercialization of an in vitro assay to help prevent birth defects. This innovative product is driven by a need to create a test for human developmental toxicity that is more accurate than current tests that use animals. False negative results from these animal assays have lead to unexpected cases of birth defects, such as observed with Thalidomide. This assay, performed on human embryonic stem cells, is more predictive of developmental toxicity than animal models (80% vs 60%) and unlike animal models, provides data about specific human biochemical pathways that are affected. This will fund research to 1) identify biomarkers of developmental toxicity present in three different human cell lines, 2) optimize automation systems, 3) create a web-based interface to be used by customers, 4) standardize and create quality control procedures and 5) take the initial steps required for validation of the assay by the European Centre for the Validation of Alternative Methods (ECVAM). Upon validation, the test will be required in Europe for assessing developmental toxicity of newly developed pharmaceuticals and may be further used for testing of environmental chemicals as well. The broader impacts of this research include 1) a global reduction in drug and chemical induced human birth defects 2) significant cost savings (up to $70 million per drug) for pharmaceutical companies allowing greater confidence in drug candidate selection and 3) a major global reduction in animal testing.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 999.94K | Year: 2010

Brain tumor stem cells (BTSCs) are a subset population within tumors that are widely believed to be responsible for tumor recurrence, due to their ability to self-renew, differentiate, migrate, and initiate tumor propagation. Given these unique features, the selective targeting of BTSCs with novel therapies may prevent tumor recurrence. Stemina will progress efforts to determine BTSC biomarkers of efficacy by assessment of additional BTSC and glioblastoma multiforme (GBM) lines for in vitro studies as well as execution of in vivo studies in this Phase II project. Specifically, Stemina proposes to increase the robustness of the Phase I in vitro studies by expanding metabolomics analysis to additional BTSC lines derived from GBM, in collaboration with the Mayo Clinic and the University of Wisconsin-Madison. Stemina will evaluate treatment efficacy in vivo using the Mayo Clinic¿s expertise in orthotopic mouse models to create in vivo models for each of the BTSC lines used in vitro. Metabolomics will be performed in plasma from these models to establish in vivo biomarkers of efficacy which will be validated and compared to in vitro biomarkers. Stemina expects to identify common biomarkers from in vitro and in vivo studies that can be translated to a commercial product.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 1.25M | 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


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 1.79M | Year: 2015

DESCRIPTION provided by applicant Autism spectrum disorder ASD is now diagnosed in of children with recent reports citing as many as in children in the United States The average age of diagnosis is more than years There is a need for a reliable biomarker based test for earlier diagnosis of ASD in young children to improve outcomes such as cognition social function and communication This will subsequently decrease the financial and emotional burden on families and society In Stemina began a self funded Phase I equivalent study of plasma samples from nearly ASD Developmental Delay DD and Typically Developing TD children From these studies we developed computational models based on metabolic biomarker differences in ASD and TD children that could differentiate ASD from TD patients with an accuracy of about Stemina seeks funding to enroll patients in a well defined clinical study to develop a biomarker based diagnostic test capable of classifying ASD relative to other developmental delays at greater than accuracy In addition we propose to identify metabolic subtypes present within the ASD spectrum that can be used for personalized treatment The study will include ASD DD and TD children between and months of age Inclusion of DD patients is a novel and important aspect of this proposed study from the perspective of a commercially available diagnostic test Our ultimate goals are to enable early diagnosis and treatment elucidate metabolic differences in subtypes of ASD patients to properly match the best available treatments for each patient from an individual biochemical perspective and identify biochemical alterations in patients across the spectrum that will provide targets for novel therapies We will employ the innovative metabolomics approaches that we developed in Phase I including coupling orthogonal chromatographic separation methodologies with both non targeted and targeted high resolution mass spectrometry Our study objectives will be to confirm biomarkers that were discovered in Phase I expand those biomarker profiles for metabolic subtypes and optimize the ASD test accuracy by creating panels of biomarker subtypes that will better describe this heterogeneous syndrome Based on our Phase I data we believe this clinical study will also allow us to confirm specific metabolic biomarkers of subtypes of ASD This innovative approach to characterizing ASD will allow physicians to suggest the most appropriate treatment based on the individual metabolism of the patient PUBLIC HEALTH RELEVANCE Stemina is developing metabolic biomarker based blood and urine diagnostic tests for autism in children between and months of age So far the tests are about accurate but need to be developed further We are asking for funding to enroll autistic developmentally delayed and typical children in a clinical study to continue our work Our ultimate goals are to enable early diagnosis and treatment find metabolic differences in of ASD patients to properly match the best available treatments for each patient and identify biochemical alterations in patients across the spectrum that will provide targets for new treatments


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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