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Nat Biotechnol. 2011 Jan;29(1):73-8. doi: 10.1038/nbt.1717. Epub 2010 Dec 12.

Genomic safe harbors permit high β-globin transgene expression in thalassemia induced pluripotent stem cells.

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  • 1Center for Cell Engineering, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

Abstract

Realizing the therapeutic potential of human induced pluripotent stem (iPS) cells will require robust, precise and safe strategies for genetic modification, as cell therapies that rely on randomly integrated transgenes pose oncogenic risks. Here we describe a strategy to genetically modify human iPS cells at 'safe harbor' sites in the genome, which fulfill five criteria based on their position relative to contiguous coding genes, microRNAs and ultraconserved regions. We demonstrate that ∼10% of integrations of a lentivirally encoded β-globin transgene in β-thalassemia-patient iPS cell clones meet our safe harbor criteria and permit high-level β-globin expression upon erythroid differentiation without perturbation of neighboring gene expression. This approach, combining bioinformatics and functional analyses, should be broadly applicable to introducing therapeutic or suicide genes into patient-specific iPS cells for use in cell therapy.

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  • Out of harm's way. [Nat Biotechnol. 2011]
PMID:
21151124
[PubMed - indexed for MEDLINE]
PMCID:
PMC3356916
Free PMC Article
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