Drug Discovery


response to drugs known to reduce the level of mutant IKBKAP splice form. Other diseases where cellular phenotypes have been observed include Huntington’s disease34; Parkinson’s disease; Long QT syndrome35; Leopard syndrome36; Pompe dis- ease37; hepatic glycogen storage disease38; and ubiquitous aspects of cardiac hypertrophic pheno- types in both ES and iPS cell-derived cardiomy- ocytes39; (Kattman et al, unpublished).


What needs to change for Pharma to implement iPSC-derived models? Even though significant progress has been made, it is likely that full adoption and general acceptance will require comparative studies, scale-up and pilot screens. There remains insufficient data demon- strating that iPS cells are superior to existing pri- mary animal cells or standard lab cell lines, though protocols for generating terminally mature, differ- entiated human cell types are progressing rapidly. Significant progress has been made in creating insulin-producing beta-cells40-41, ventricular car- diomyocytes42, P450-expressing hepatocytes43, specific neuronal populations44, and retinal pho- toreceptors45, to name just a few. Once these pro- tocols are established, technology for scale up will be required that maintains a cell’s phenotype, shows batch-to-batch consistency and reproducibil- ity, and is cost-effective for the industry. Given the intensive research efforts ongoing in academic labs to improve protocols and in biotechnology compa- nies to scale cells, there is reason for optimism that iPS cells will be used in the lab either alongside or as replacements for traditional cell lines.


What’s the future vision for iPS cells? iPS cells may have a profound impact on drug dis- covery, either in the generation of previously unob- tainable cellular disease model systems for small molecule screening; mechanism of action studies; or highly predictable, animal-free systems for determining drug safety. One can envisage a screen of genetic diversity panels of cardiomyocytes or hepatocytes to identify rare responders, analyse drug effects on complex 3D organ systems, or per- form ‘clinical trials’ using iPS-derived diseased cells where safety, efficacy, dosage studies, and the effect of genetics could be studied before initiating Phase I studies in patients. Another potential application will be use of iPS-derived cells and/or genetically- modified iPS cells in transplantation where there may be immunological advantages for organ engraftment. Proof of concept is now well-docu- mented in pre-clinical models of retinal dystro- phy46, in reversal of liver damage47, and in diabet-


Drug Discovery World Winter 2010/11


ic mouse models48. Full adoption of stem cell tech- nologies will require generation of iPS cells that are safe, stable and efficacious. The use of iPS cells for transplantation, potentially coupled with gene therapy, may usher in the era of true personalised medicine for patients with high unmet needs.


Acknowledgements


The authors would like to thank Blake Anson and Joleen Rau from Cellular Dynamics International, Madison, WI, for extensive discussions, helpful advice and critical review of the document; as well as Jason Gardner and Aaron Chuang (Stem Cell Discovery Performance Unit, GlaxoSmithKline) for their insight and comments.


DDW


Continued from page 35


Dr Julie Holder has been involved in early discov- ery and development and late stage drug discovery throughout her GSK career. Julie is currently Director of Preclinical in the Stem Cell Discovery Performance Unit at GSK and has direct experi- ence working with Mesenchymal Stem Cells (MSC) and extensive experience of compound develop- ment. She holds a PhD in Biochemistry from Leeds University, UK.


Dr Dwight Morrow is Director of Discovery in the Stem Cell Discovery Performance Unit at GSK and has extensive experience in cell-based assays, high throughput screening, and compound profiling (SAR). He received his PhD in Molecular Biology from Case Western Reserve University and did his post-doctoral work at Johns Hopkins University School of Medicine.


15 Utikal, J, Maherali, N, Kulalert, W and Hochedlinger, K. (2009). Sox2 is dispensable for the reprogramming of melanocytes and melanoma cells into induced pluripotent stem cells. J Cell Sci 122(Pt 19):3502-10. 16 Loh, YH, Agarwal, S, Park, IH, Urbach, A, Huo, H, Heffner, GC, Kim, K, Miller, JD, Ng, K and Daley, GQ. (2009). Generation of induced pluripotent stem cells from human blood. Blood 113(22):5476-9. 17 Loh, YH, Hartung, O, Li, H, Guo, C, Sahalie, JM, Manos, PD, Urbach, A, Heffner, GC, Grskovic, M, Vigneault, F, Lensch, MW, Park, IH, Agarwal, S, Church, GM, Collins, JJ, Irion, S and Daley, GQ. (2010). Reprogramming of T cells from human peripheral blood. Cell Stem Cell 7(1):15-9. 18 Seki, T, Yuasa, S, Oda, M, Egashira, T, Yae, K, Kusumoto, D, Nakata, H, Tohyama, S, Hashimoto, H, Kodaira, M, Okada, Y, Seimiya, H, Fusaki, N, Hasegawa, M and Fukuda, K. (2010). Generation of induced pluripotent stem cells from human terminally differentiated circulating T cells. Cell Stem Cell 7(1):11-4. 19 Brown, ME, Rondon, E, Rajesh, D, Mack, A, Lewis, R, Feng, X, Zitur, LJ, Learish, RD and Nuwaysir, EF. (2010). Derivation of induced pluripotent stem cells from human peripheral blood T lymphocytes. PLoS One 5(6):e0011373. 20 Kim, K, Doi, A, Wen, B, Ng, K, Zhao, R, Cahan, P, Kim, J, Aryee, MJ, Ji, H, Ehrlich, LI, Yabuuchi, A, Takeuchi, A, Cunniff, KC, Hongguang, H, McKinney-Freeman, S, Naveiras, O, Yoon, TJ, Irizarry, RA, Jung, N, Seita, J, Hanna, J, Murakami, P, Jaenisch, R, Weissleder, R, Orkin, SH, Weissman, IL, Feinberg, AP and Daley, GQ. (2010). Epigenetic memory in induced pluripotent stem cells. Nature. 467(7313):285-90.


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