Ethnically Diverse iPSC-Cardiomyocyte Panel for Pharmacogenomics and Drug Safety Testing
NIH
GREENSTONE BIOSCIENCES, INC.
PROJECT SUMMARY 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. 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.
SBIR/STTR