CRISPR/Cas9-based genetic correction for recessive dystrophic epidermolysis bullosa View Full Text


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Article Info

DATE

2016-12-08

AUTHORS

Beau R Webber, Mark J Osborn, Amber N McElroy, Kirk Twaroski, Cara-Lin Lonetree, Anthony P DeFeo, Lily Xia, Cindy Eide, Christopher J Lees, Ron T McElmurry, Megan J Riddle, Chong Jai Kim, Dharmeshkumar D Patel, Bruce R Blazar, Jakub Tolar

ABSTRACT

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe disorder caused by mutations to the COL7A1 gene that deactivate production of a structural protein essential for skin integrity. Haematopoietic cell transplantation can ameliorate some of the symptoms; however, significant side effects from the allogeneic transplant procedure can occur and unresponsive areas of blistering persist. Therefore, we employed genome editing in patient-derived cells to create an autologous platform for multilineage engineering of therapeutic cell types. The clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 system facilitated correction of an RDEB-causing COL7A1 mutation in primary fibroblasts that were then used to derive induced pluripotent stem cells (iPSCs). The resulting iPSCs were subsequently re-differentiated into keratinocytes, mesenchymal stem cells (MSCs) and haematopoietic progenitor cells using defined differentiation strategies. Gene-corrected keratinocytes exhibited characteristic epithelial morphology and expressed keratinocyte-specific genes and transcription factors. iPSC-derived MSCs exhibited a spindle morphology and expression of CD73, CD90 and CD105 with the ability to undergo adipogenic, chondrogenic and osteogenic differentiation in vitro in a manner indistinguishable from bone marrow-derived MSCs. Finally, we used a vascular induction strategy to generate potent definitive haematopoietic progenitors capable of multilineage differentiation in methylcellulose-based assays. In totality, we have shown that CRISPR/Cas9 is an adaptable gene-editing strategy that can be coupled with iPSC technology to produce multiple gene-corrected autologous cell types with therapeutic potential for RDEB. More... »

PAGES

16014

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/npjregenmed.2016.14

    DOI

    http://dx.doi.org/10.1038/npjregenmed.2016.14

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1046822100

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/28250968


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