Induced pluripotent stem cells (iPSCs), derived from adult somatic cells, have the potential to streamline the inefficient and expensive method of drug discovery. Recent advances in high-throughput screening techniques have enabled researchers to generate tens of thousands of potential drug candidates. Before any one candidate advances to the preclinical or clinical-trial stage, however, the whole cohort is screened— using cell-based assays—to identify candidates with the best therapeutic potential. Historically, continuous cell lines have been the preferred substrate for these tests because they are homogenous and can be obtained in large enough quantities to support the substantial needs of the assays. Unfortunately, in most cases, continuous cell lines are not faithful representations of the physiological state of the target cell or disease state, which may result in poor therapeutic candidates advancing to the preclinical stage.
iPSCs, on the other hand, can be generated from the diseased tissue itself and will therefore provide a better cellular substrate for screening the cohort. First, however, researchers must develop a method to completely reprogram somatic cells and then reliably differentiate them into a particular cell type. Early methods of reprogramming somatic cells involved using viral vectors to induce expression of several critical transcription factors (Oct3/4, Sox2, c-Myc and Klf4). This method, while largely effective, left the cells vulnerable to insertional mutagenesis. Currently, investigators are attempting to circumvent methods that involve genomic modifications by reprogramming cells using mRNAs or small molecules. If successful, these methods will allow researchers to build large collections of cells (e.g., skin cells) from individuals with a specific disease (e.g., ALS), reprogram and expand them, and then differentiate them into the cell type(s) (e.g., neurons) of interest.
Using cells differentiated from individuals with a specific disease,as a substrate for cell based assays will afford a more physiologically relevant characterization of a drug candidate’s therapeutic potential. Investigators will be able to make better decisions about which candidates to advance to preclinical trials. In the end, iPSC-based assays will improve the rate of solidly performing drugs that advance through the process, reduce costs, and ultimately transform the way researchers approach drug discovery.