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Platform for the generation of integration free pluripotent stem cells.

Awarded: NOK 8.0 mill.

Project Number:


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Project Period:

2012 - 2017

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Induced pluripotent stem cells (iPSCs) are produced from mammalian somatic cells by reprogramming the cell to a so call pluripotent state via the introduction of key genes or the regulators such as microRNA that promote the process. iPSCs provide an unlimited supply of cells due to there ability to self renew indefinitely and importantly,can be coaxed into potentially any cell type due to being pluripotent. As a consequence, iPSCs are being developed to provide alternative sources of cells for therapy in clinical medicine. In addition, iPSCs derived from patients can provide a powerful tool for dissecting disease pathogenesis and the effects of drugs both at the individual and disease level due to prior knowledge of the genetic status of the donor ? a step closer to personalized medicine. We have seen some very interesting alternative uses of this technology including the derivation of iPSCs from endangered species and farm animals. To this point there have been efforts to provide methodologies that are robust and reproducible to provide high quality iPSCs that can potentially be translated to the clinic i.e. GMPable. There has been intense research to address this, and there have been a number of methodologies developed to date, including protein based reprogramming that generate high quality iPSCs but with abysmal reprogramming efficiencies combined with being extremely labour intensive. To address this, our project provides a solution to this problem! We are developing a platform that initially will be utilised to generate iPSCs but can be easily modified to be useful in transdifferentiation and protein delivery in general. The system is based upon producing a feeder layer that provide the necessary machinery (proteins) that can provide the environment to change cellular fate. The feeder layer will secrete the gene products via a signal peptide that effectively exports the protein from the cell combined with another signal peptide that facilitates efficient uptake. This will negate the requirement of generating recombinant proteins and adding these daily over many weeks. This will be combined with already established conditions to maximise iPSC production using a combination of small molecules and siRNA. This simple method will be amenable to automation and potentially cells could be engineered from the donor and used to reprogramme their own cells! This methodology will provide a useful tool to potentially aid the simple production of high quality, iPSCs in and efficient manner.

Current models employed by the pharmaceutical industry and academia to investigate disease, drug discovery/ safety/ efficacy, and toxicity are inadequate, as they do not faithfully recapitulate the human physiology, metabolism or cellular behavior. Conseq uently, there is a pressing need to improve this. With the recent development of human induced pluripotent stem cell (hiPSC) technology, this provides a novel way to model human disease and offers an alternative to current cell-based systems, most importa ntly as a potentially limitless supply of genetically defined stem cells that can be potentially differentiated into any cell type under defined conditions. This also decreases dependency, usage and overall numbers of animal models, in compliance with the 3R?s (Reduction, Refinement and Replacement). Current hiPSC technology itself has its own limitations, which include the use of lenti-/ retroviral approaches that lead to unwanted perturbation of the genome, therefore the key challenge to address is the establishment of non-integrative methods of reprogramming, that will allow the potential use of the derived hiPSCs in disease modelling, toxicity studies, drug discovery/ safety/ efficacy and in the long term, potential therapuetic application. This in tu rn will lead to potential platforms that could be utilized to reprogramme somatic cells to not only pluripotency but to progenitor populations or transdifferentiate to other somatic cell types which are not easily obtained!

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