
TempO-Seq assay and cell panel for assessing impact of genetic diversity on compound bioactivity and toxicity riskAward last edited on: 4/9/2022
Sponsored Program
SBIRAwarding Agency
NIH : NIEHSTotal Award Amount
$252,121Award Phase
1Solicitation Topic Code
113Principal Investigator
Bruce E SeligmannCompany Information
Phase I
Contract Number: 1R43ES032514-01Start Date: 1/1/2021 Completed: 7/31/2022
Phase I year
2021Phase I Amount
$252,121Public Health Relevance Statement:
Narrative: This Phase I project will demonstrate the feasibility of using expression profiling for assessing the impact of genetic variation on response to compound exposure and inferences to the corresponding risk of toxicity across the human population. Using the TempO-Seq S1500 surrogate human whole transcriptome assay to profile all known biochemical pathways, together with HepaRG cells harboring knockouts of major xenobiotic clearance pathway genes, 3D HEPATOPAC co-cultures of primary human hepatocytes from donors with varying compound responses, and a set of reference compounds with known modes of action, compound- specific signatures and toxicity pathways will be identified for each genetic variant using DESeq2 and Pathway analysis, then quantified using BMDExpress to determine the benchmark concentration (BMC) for each modulated pathway and gene to define differences between variants in metabolism, exposure level, and toxicity pathways and dose. Once feasibility is demonstrated in Phase I, the use of the HEPATOPAC and HepaRG cell systems and the TempO-Seq assay will be marketed, an expanded panel of variant HepaRG variants and/or HEPATOPAC cultures will be established, and test process validated and commercialized in Phase II, so that the in vitro impact of genetic variability across the population on exposure and toxicity of test agents can be determined and used for in vitro-to-in vivo extrapolation of exposure risk of genetically diverse individuals.
Project Terms:
CYP3A4 ; Cytochrome P450 3A4 ; Cytochrome P450, Subfamily IIIA, Polypeptide 4 ; Cytochrome P450PCN1 ; FAMILY III P450 ; Glucocorticoid-Inducible P450 ; Nifedipine Oxidase ; P450C3 ; P450PCN1 ; Steroid-Inducible P450- III ; CYP3A4 gene ; ABC15 ; ABCG2 ; ABCP ; ATP-Binding Cassette, Sub-Family G (WHITE), Member 2 Gene ; ATP-Binding Cassette, Sub-Family G, Member 2 ; ATP-Binding Cassette, Subfamily G, Member 2 ; BCRP ; BCRP1 ; Breast Cancer Resistance Protein ; EST157481 ; MRX ; MXR1 ; Mitoxantrone Resistance Protein ; Placenta-Specific ATP-Binding Cassette Transporter ; ABCG2 gene ; CYP2C ; CYP2C19 ; Cytochrome P450, Subfamily IIC, Polypeptide 19 ; Mephenytoin 4-Prime Hydroxylase ; P450C2C ; CYP2C19 gene ; CYP2C9 ; Cytochrome P450, Subfamily IIC, Polypeptide 9 ; CYP2C9 gene ; CPD6 ; CYP 2D6 ; CYP2D ; CYP2D6 ; CYP2DL1 ; CYPIID6 ; Cytochrome P-450 CYP2D6 ; Cytochrome P450 2D6 ; Cytochrome P450 Subfamily IID Polypeptide 6 ; Debrisoquine 4-Hydroxylase ; Debrisoquine 4-Monooxygenase ; Debrisoquine Hydroxylase ; Imipramine 2-Hydroxylase ; P450-2D6 ; P450-DB1 ; P450C2D ; P450DB1 ; Sparteine Monooxygenase ; Subfamily IID Cytochrome P450 ; Subfamily IID-Like 1 Cytochrome P450 ; CYP2D6 gene ; Dose ; Data ; Molecular Toxicology ; Proliferating ; in vitro Assay ; in vivo ; Cellular Assay ; cell assay ; Scientific Advances and Accomplishments ; scientific accomplishments ; scientific advances ; Molecular ; Knock-out ; Knockout ; Process ; Pathway interactions ; pathway ; genetic variant ; Gene variant ; allele variant ; allelic variant ; genomic variant ; Population ; innovation ; innovate ; innovative ; transcriptome ; global gene expression ; global transcription profile ; gene product ; three dimensional cell culture ; 3D cell culture ; 3D culture ; Expression Profiling ; in vivo evaluation ; in vivo testing ; phase 2 testing ; phase 2 evaluation ; phase II evaluation ; phase II testing ; Affect ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Budgets ; Cell Differentiation process ; Cell Differentiation ; Cell Line ; CellLine ; Strains Cell Lines ; cultured cell line ; Cells ; Cell Body ; Cultured Cells ; Gene Expression ; Genes ; Goals ; Human ; Modern Man ; In Vitro ; Literature ; Metabolism ; Intermediary Metabolism ; Metabolic Processes ; Mus ; Mice ; Mice Mammals ; Murine ; Persons ; Oligonucleotides ; Oligo ; oligos ; Publishing ; Risk ; Safety ; Specificity ; Testing ; Transferase ; Transferase Gene ; Genetic Variation ; Genetic Diversity ; Xenobiotics ; Measures ; 3T3 Cells ; Risk Assessment ; Stromal Cells ; Guidelines ; base ; detector ; Phase ; Variant ; Variation ; Hepatocyte ; Hepatic Cells ; Hepatic Parenchymal Cell ; Liver Cells ; Individual ; Policies ; ATP-Binding Cassette Transporters ; ABC Transport Protein ; ABC Transporter Protein ; ABC Transporters ; Toxicity Tests ; Toxicity Testing ; Biochemical Pathway ; Metabolic Networks ; Toxicokinetics ; Coculture Techniques ; Co-culture ; Cocultivation ; Coculture ; Metabolic ; Genetic ; gene function ; Exposure to ; tool ; programs ; System ; 3-D ; 3D ; three dimensional ; 3-Dimensional ; Best Practice Analysis ; Benchmarking ; success ; Toxicities ; Toxic effect ; expectation ; novel ; Binding Site Domain ; Ligand Binding Domain ; General Public ; General Population ; Gene Expression Monitoring ; Gene Expression Pattern Analysis ; Transcript Expression Analyses ; Transcript Expression Analysis ; gene expression analysis ; gene expression assay ; transcriptional profiling ; Gene Expression Profiling ; Network Analysis ; Pathway Analysis ; Modeling ; response ; cross reactivity ; Pharmacogenomics ; CP34 ; CYP3 ; CYP3A ;
Phase II
Contract Number: ----------Start Date: 00/00/00 Completed: 00/00/00