Drug Discovery
induced pluripotent
stem cells a model for transforming drug discovery
Induced pluripotent stem (iPS) cells have the potential to transform drug discovery by providing physiologically relevant cells for toxic compound identification, target validation, compound screening, and tool discovery. The technology for generating iPS cells is advancing rapidly, as is the repertoire of cell types that can be differentiated. Tissue-specific cells derived from iPS cells are currently being evaluated by the pharmaceutical industry for their utility in identifying cardiotoxic and hepatotoxic compounds as therapeutically relevant systems for modelling cardiovascular diseases, neurodegenerative disorders and metabolic disorders, as well as for generating patient-specific cell types. In order to fully capitalise on the rapidly evolving science of iPS cell technology, pharma will need to leverage the expertise found in academia and biotechnology companies to apply iPS-derived cells in an industrial setting. This review will summarise the potential of these cells as well as highlight many of the challenges that remain.
S
tem cells are a distinct self-replenishing cell population whose primary function is to generate progeny that then develop into ter- minally differentiated cell types, such as a car- diomyocytes, neurons or photoreceptors. Tissue- specific adult stem cells, or progenitors, are com- mitted to producing tissue or lineage-specific cells, whereas totipotent or pluripotent stem cells can give rise to any of the 200+ cell types of the body. There are two types of pluripotent stem cells defined by their tissue origin: 1) embryonic stem (ES) cells obtained from early embryos, typically at the blastula stage, and 2) induced pluripotent stem (iPS) cells derived through a reprogramming process whereby terminally differentiated somatic cells are reprogrammed or induced to a pluripo- tent state (Figure 1).
Drug Discovery World Winter 2010/11
Successful generation of human iPS cells was reported independently in 2007 by the research groups of Drs James Thomson and Shinya Yamanaka1,2. Both groups successfully identified a minimum number of nuclear factors that could reprogramme terminally differentiated fibroblasts to pluripotent cell lines by exogenously expressing distinct yet overlapping sets of genes: Yu and col- leagues used Oct4, Sox2, Nanog and Lin28 by lentiviral gene transfer, while Yamanaka and col- leagues employed Oct4, Sox2, Klf4 and c-Myc via retroviral gene transfer. These landmark studies were a significant advance over whole nucleus reprogramming3 and have had several important consequences. Induced pluripotent stem cell tech- nology does not require human embryos and thus circumvents the ethical issues associated with
By Dr Dwight Morrow and Dr Julie Holder
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