Phase I Amount
$1,294,681
Cardiotoxicity is a leading cause of early and late-stage drug attrition during pharmaceutical development. The FDA now mandates that all new drugs be tested for cardiotoxicity before entering clinical trials. However, there needs to be a safety screening platform that can swiftly detect cardiotoxicity cost-effectively, even before investing too much time and resource in a drug development pipeline. This is further complicated by genomic susceptibility in the population and how they respond to drugs. A tool that can incorporate the influences of sex, ethnicity, and genetic background can provide accurate data on the safety and efficacy of drugs and stratify patient populations to identify responders versus non-responders. In this SBIR grant, we propose to mitigate this issue by providing pharmacogenomics and precision medicine platforms using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Our product is a kit comprising 100 unique and ethnically diverse iPSC lines with equal sex representation. We aim to develop and validate this tool as a surrogate in vitro model for predicting drug toxicity in patient groups at high risk for drug-induced arrhythmia. The study will use the "cell village" platform to co-culture 10 different patient-specific iPSC lines simultaneously. We will scale this up by multiplexing data from 100 different donors to identify cell-type-specific expression quantitative trait loci (eQTL) using single-cell RNA sequencing (scRNA-seq) and whole genome sequencing (WGS). As a proof-of-principle, we will also assess inter-individual and intra-individual variability in responses to the chemotherapeutic agent doxorubicin. Finally, Greenstone Biosciences, Inc is a biotechnology company located at the Stanford Research Park. Greenstone uses latest advances in clinical genomics, computational biology, and patient-specific iPSCs to understand pharmacogenomics and to accelerate drug discovery.
Public Health Relevance Statement: NARRATIVE All new drug candidates must be screened for potential cardiac toxicities before being given to patient. Current drug screening technologies fail to consider the differences between men and women, and differences between different ethnic groups or the fact that people with genetic cardiac abnormalities account for most drug failures; this results in an enormous cost in terms of late-stage drug development failures and patient morbidity/mortality. Greenstone Biosciences has the world's largest collection of induced pluripotent stem cell lines, and the purpose of this application is to develop a subset of these into a validated panel for drug screening and drug discovery that for the first time reflects the heterogeneity of the population at large.
Project Terms: Acceleration; ages; Age; American Heart Association; Anthracycline; Arrhythmia; Cardiac Arrhythmia; Heart Arrhythmias; Biological Sciences; Biologic Sciences; Bioscience; Life Sciences; Biotechnology; Biotech; Calcium; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Cardiovascular Agents; Cardiovascular Drugs; Cardiovascular system; Cardiovascular; Cardiovascular Body System; Cardiovascular Organ System; Heart Vascular; circulatory system; Cell Line; CellLine; Strains Cell Lines; cultured cell line; Cell Survival; Cell Viability; Cells; Cell Body; Client; Clinical Trials; Communities; Cryopreservation; Cryofixation; cold preservation; cold storage; Dedications; Disease; Disorder; DNA Damage; DNA Injury; Doxorubicin; 14-Hydroxydaunomycin; Adriamycine; Doxorubicina; Hydroxyl Daunorubicin; Hydroxyldaunorubicin; Drug Industry; Pharmaceutic Industry; Pharmaceutical Industry; Pharmacotherapy; Drug Therapy; drug treatment; Drug toxicity; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Economics; economic; Electrophysiology (science); Electrophysiology; Neurophysiology / Electrophysiology; electrophysiological; Ethnic Population; Ethnic Group; Ethnic People; Ethnic individual; Ethnicity People; Ethnicity Population; ethnic subgroup; ethnicity group; Gene Expression; Population Genetics; Grant; Health Personnel; Health Care Providers; Healthcare Providers; Healthcare worker; health care personnel; health care worker; health provider; health workforce; healthcare personnel; medical personnel; treatment provider; Human; Modern Man; Investments; Karyotype determination procedure; Karyotyping; Karyotyping Genetics; Laboratories; Libraries; Marketing; men; Metabolism; Intermediary Metabolism; Metabolic Processes; Morbidity - disease rate; Morbidity; mortality; Persons; Patients; Pharmacy (field); Pharmaceutics; pharmaceutic; Production; Research; Research Personnel; Investigators; Researchers; Resources; Research Resources; Risk; Safety; Sarcomeres; Technology; Testing; Time; Translating; Caucasians; Caucasian; Caucasian Race; Caucasoid; Caucasoid Race; Occidental; white race; Woman; Work; diverse populations; heterogeneous population; population diversity; Population Heterogeneity; Active Oxygen; Oxygen Radicals; Pro-Oxidants; Reactive Oxygen Species; dosage; Area; Clinical; Medical; Ensure; Evaluation; Susceptibility; Predisposition; Cardiac Muscle Cells; Cardiocyte; Heart Muscle Cells; Heart myocyte; cardiomyocyte; Cardiac Myocytes; Failure; Individual; Toxicity Testing; Toxicity Tests; Ethnicity; Ethnic Origin; Collaborations; Co-culture; Cocultivation; Coculture; Coculture Techniques; Metabolic; Genetic; tool; Computational Biology; computer biology; Hour; Protocols documentation; Protocol; cell type; Pattern; interest; Quantitative Trait Loci; QTL; drug efficacy; professor; Reporting; chemotherapeutic agent; Modeling; Sampling; response; drug development; Cardiotoxicity; Cardiac Toxicity; Cardiotoxic; Genomics; drug discovery; Antineoplastic Protocols; Cancer Treatment Protocols; Transcription Initiation Site; Transcription Start Site; Pharmacogenomics; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; pharmaceutical; Pharmacologic Substance; genome sequencing; Dose; Breast Cancer Treatment; Data; in vitro Model; Collection; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; South Asian; Characteristics; sex; Cardiac; Development; developmental; Image; imaging; cost; computer based prediction; prediction model; predictive modeling; scale up; Population; transcriptomics; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapy; novel therapeutics; iPS; iPSC; iPSCs; induced pluripotent cell; inducible pluripotent stem cell; induced pluripotent stem cell; high risk; patient population; genome scale; genomewide; genome-wide; safety testing; drug candidate; screenings; screening; precision-based medicine; precision medicine; multielectrode arrays; multi-electrode arrays; multiomics; multiple omics; Cardiac Abnormalities; Cardiac Malformation; Cardiac defect; Heart Malformation; heart defect; Heart Abnormalities; stratified patient; patient stratification; responders from non-responders; responders or non-responders; responders versus non-responders; responders vs non-responders; responders and non-responders; inter-individual variability; interindividual variability; interindividual variation; inter-individual variation; entire genome; full genome; whole genome; ethnically diverse; ethnic diversity; Drug Screening; individual heterogeneity; individual variability; individual variation; scRNA-seq; single cell RNA-seq; single cell RNAseq; single cell expression profiling; single cell transcriptomic profiling; single-cell RNA sequencing; side effect; drug safety; pharmaceutical safety; medication safety; East Asian; induced pluripotent stem cell derived cardiomyocytes; iPS cell derived cardiomyocytes; iPSC derived cardiomyocytes; Hispanic Populations; Hispanic group; Hispanic individual; Hispanic people; Hispanics; African American population; African American group; African American individual; African American people; African Americans; patient retention
