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Plos Biology : Generation of Healthy Mice from Gene-corrected Disease-specific Induced Pluripotent Stem Cells, Volume 9

By Goodell, Margaret A.

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Book Id: WPLBN0003952206
Format Type: PDF eBook :
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Reproduction Date: 2015

Title: Plos Biology : Generation of Healthy Mice from Gene-corrected Disease-specific Induced Pluripotent Stem Cells, Volume 9  
Author: Goodell, Margaret A.
Volume: Volume 9
Language: English
Subject: Journals, Science, Biology
Collections: Periodicals: Journal and Magazine Collection (Contemporary), PLoS Biology
Historic
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Publisher: Plos

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Goodell, M. A. (n.d.). Plos Biology : Generation of Healthy Mice from Gene-corrected Disease-specific Induced Pluripotent Stem Cells, Volume 9. Retrieved from http://netlibrary.net/


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Description : Using the murine model of tyrosinemia type 1 (fumarylacetoacetate hydrolase [FAH] deficiency: FAH2/2 mice) as a paradigm for orphan disorders, such as hereditary metabolic liver diseases, we evaluated fibroblast-derived FAH2/2-induced pluripotent stem cells (iPS cells) as targets for gene correction in combination with the tetraploid embryo complementation method. First, after characterizing the FAH2/2 iPS cell lines, we aggregated FAH2/2-iPS cells with tetraploid embryos and obtained entirely FAH2/2-iPS cell–derived mice that were viable and exhibited the phenotype of the founding FAH2/2 mice. Then, we transduced FAH cDNA into the FAH2/2-iPS cells using a third-generation lentiviral vector to generate genecorrected iPS cells. We could not detect any chromosomal alterations in these cells by high-resolution array CGH analysis, and after their aggregation with tetraploid embryos, we obtained fully iPS cell–derived healthy mice with an astonishing high efficiency for full-term development of up to 63.3%. The gene correction was validated functionally by the long-term survival and expansion of FAH-positive cells of these mice after withdrawal of the rescuing drug NTBC (2-(2-nitro-4- fluoromethylbenzoyl)-1,3-cyclohexanedione). Furthermore, our results demonstrate that both a liver-specific promoter (transthyretin, TTR)-driven FAH transgene and a strong viral promoter (from spleen focus-forming virus, SFFV)-driven FAH transgene rescued the FAH-deficiency phenotypes in the mice derived from the respective gene-corrected iPS cells. In conclusion, our data demonstrate that a lentiviral gene repair strategy does not abrogate the full pluripotent potential of fibroblast-derived iPS cells, and genetic manipulation of iPS cells in combination with tetraploid embryo aggregation provides a practical and rapid approach to evaluate the efficacy of gene correction of human diseases in mouse models.

 

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