Human Disease-Specific Induced Pluripotent Stem Cells For Preclinical Drug Testing and Drug Discovery

ABSTRACTDrug-induced adverse cardiac effects are a leading cause of drug attrition during pharmaceutical development. In recent years, the withdrawal of several cardiac and non-cardiac drugs from the market due to unpredicted cardiotoxicity has imposed a multibillion-dollar burden on the pharmaceutical industry. As a result, FDA now mandates that all new drugs be tested for cardiotoxicity before entering clinical trials. However, there is still a lack of appropriate safety screening platforms that can accurately predict the proarrhythmic liability of new chemical entities; in particular there are no validated commercial platforms that address the diverse patient population with regard to sex, ethnicity or genetic susceptibility to drug-induced cardiotoxicity.The company is developing a select subset of fifty cell lines from healthy subjects as well as from patients with common hereditary cardiac disorders such as familial hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and long QT syndrome (LQTS), to predict individual and group differences in drug susceptibility to cardiotoxicity. As female sex is an independent risk factor for drug-induced cardiac arrhythmias and women comprise more than 50% of the population, a major focus of this research project will be to quantify the extent gender factors in drug-induced proarrhythmia. Each cell line will be validated functional and pharmacologically. This panel of cell lines will be unique in terms of its breadth and detailed (anonymized) patient and genetic data for each line. While some competing companies cell one or two lines, they do not perform services and do not include the detailed patient and genetic data available to Khloris. Khloris Biosciences is a start-up company based in the Bay Area. Khloris was co-founded by Dr. Joseph Wu (Stanford University) and has worldwide exclusive rights to the world’s largest collection of patient-derived iPSC-CMs developed in his laboratory as well as the anonymized genetic and pathological characterization of each line.The purpose of the current SBIR application is to greatly expand the current offering of Khloris to include a large and diverse collection of validated cell lines comprising male AND female derived disease-specific iPSC- CMs from patients with common hereditary cardiac disorders and genetic backgrounds. We aim to develop and validate this tool as a surrogate in vitro model for prediction of cardiac drug toxicity in patient groups at high risk for drug-induced arrhythmia. Khloris believes this platform will revolutionize drug discovery and development by reassigning the thresholds for cardiotoxicity, thereby reducing the possibility of mistakenly eliminating promising candidates, expediting the advancement of worthy drugs to clinic and discovering new cardiovascular drugs.