arnessing the Power of High-Throughput RNAi Prospects and Practicalities Pathfinder

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1 arnessing the Power of High-Throughput RNAi Prospects and Practicalities Pathfinder Innovative high-throughput (HT) solution for rational drug discovery Masato Miyake, Ph.D, CSO, CytoPathfinder, Inc. June 8, 2006 Hyatt Harborside at Logan International Airport, Boston, MA, USA

2 Pathfinder Established: Dec. 20, 2004 CytoPathfinder Capital: JPY160.6 Million Management: Yoshiji Fujita, Ph.D (President & CEO) Kazuyuki Masuda, Ph.D MBA (Deputy President, CFO) Naoto Kagiyama, Ph.D (CTO) Masato Miyake, Ph.D (CSO) Auditor: Toshio Koshiishi, Mikio Takahashi Location: AIST Tsukuba central , Tsukuba Ibaraki, Japan

3 Pathfinder CytoPathfinder is a bio-venture specializing in technologies based on an unique transfection microarray system and original DDSs. We are committed to the R&D of innovative pharmaceutical products through the comprehensive functional analysis of genes in various cellular systems.

4 Pathfinder Key technology: Transfection microarray DNA* microarray for multiple gene transfection for various kinds of mammalian cells. HT transfection format with easy handling. Extremely high transfection efficiency comparison with ordinary Lipid and/or Polymer-mediated transfection procedures. * Plasmid DNA, sirna etc.

5 Transfection microarray (TMA) realizes the best cenario of genome-wide functional screening Biopsy enome-wide screening Reliability Reproducibility Transfection difficulty Limitation of cell source Targets Primary cells Varidation by primary cells Reality: Efficacy is the major reason of drop out at the late stage. Phase Phase Data source:suter et al., Chemistry & Biology Vol. 11, (Feb. 2004) Disease models Conventional strategy Immortarized cell lines Large-scale culture sirna Genome-wide functional screening The cell-line sometimes shows different profile of function from the primary cells. Does the candidate set involve the best target? Pathfinder

6 Three parameters toward successful functional screening Transfection accelerator Efficiency Control of release rate Localization Homogeneity Control of liquid property of Transfection mixture Pathfinder

7 Analysis of TMA Scanning Image analysis Quantification

8 Pathfinder CytoPathfinder s system open the way Transfection Efficiency Low transfection efficiency Limitation of cell resource Throughput Scale up & HT difficulties Complicated and troublesome to handling High cost Cell-based functional assay Transfection accelerators On-chip miniaturized transfection Unique data analysis over 10 times Higher transfection efficiency Easy to adapt primary/normal cell over 100 times Easy to handling High reliability Low cost HT format Original analysis algorism and database for multiple assay and cellular event

9 Data integration for target identification Biological data integration P Common gene and pathway for efficacy P Comparative network analysis P Comprehensive Functional assay Text-based interaction mining Relational analysis Cell death Cell death SK-BR-3 T-47D 1-5 genes genes 200 genes Gene expression profiling In the presence or absence of DXR Genome sequence 200 genes genes Pathfinder

10 Pathfinder Conclusion Drug Profiling Target Validation Problems s in Genome-wide sirna screening Reliability Reproducibility Transfection difficulty Limitation of cell source For Genome-wide trials DNA microarray Real Real-time PCR Protein chip cdna library expression Exogenous gene expression Gene knock-down etc

11 Acknowledgements CytoPathfinder Tomohiro Yoshikawa, Ph.D Takanori Ueda, Ph.D Michiko Kishi Noriko Araki Mie Ikegami National Institute of Advanced Industrial Science & Technology Jun Miyake, Ph.D Satoshi Fujita, Ph.D Shigeru Yamada, Ph.D Eiichiro Uchimura, Ph.D Masaaki Uchida, Ph.D Eiji Ohta, Ph.D Daniel P. Funeriu, Ph.D Nihon Schering KK Research Center Kazuhiro Sakurada, Ph.D Tetsuya Ishikawa, Ph.D Shinobu Suzuki, Ph.D Hiromi Terami, Ph.D Noriko Sakai University of Tokyo Teruyuki Nagamune, Ph.D Kouichi Kato, Ph.D