Phenotypic Drug Discovery using patient-iPSCs derived from a rare disease of Pompe
Wednesday, February 7
2:30 PM - 3:00 PM
Center for iPS Cell Research and Application (CiRA), Kyoto University
Recent advances in the development of induced pluripotent stem cell (iPSC) technology, gene editing tools, imaging assay technologies, etc. have led to increased interest in phenotypic drug discovery (PDD) approaches. In particular, human iPSCs can generate human ’disease in a dish’. Also, iPSCs have many advantages such as human origin, easy accessibility, scalability, ability to produce the desired cells, and the possibility to develop personalized medicines with patient-iPSCs. Nevertheless, few pharmaceutical companies have introduced drug discovery using iPSC technology. This is because iPSC technology still has many problems which include cost, reproducibility, batch to batch variation and differentiation. Center for iPS Cell Research and Application (CiRA), Kyoto University are currently working on solving these problems.In this presentation, we picked up our pilot study of PDD using iPSC, which is Pompe disease project. Pompe disease is a rare inherited metabolic disease of lysosomal glycogen accumulation due to dysfunction of acid alpha-glucosidase (GAA). Current therapy is a replacement enzyme therapy of its lysosomal enzyme, but it does not completely recover in the skeletal muscle function. Recently it was reported to be caused by dysfunction of autophagy and lysosomes. So, we developed an HTS-compatible screening system focusing on autophagy. For a preparation of patient relevant myocytes, we established a robust and scalable differentiation system by forced expression of MyoD (master regulator of muscle differentiation). Using this, we screened around 5000 compounds (FDA-approved drugs and bioactive compounds) and found several candidates. Next, we evaluated them for other functional assays and predicted the mechanism of action (MoA) of candidate compounds by identifying drug-specific gene expression signatures using RNA-seq. These compounds we discovered could be applied to drug repurposing and lead to clinical translation. In conclusion, we believe that PDD using iPSC technology is a powerful approach to identify novel MoAs and therapies, especially for drug discovery of rare diseases.