Abstract
Patients with recessive dystrophic epidermolysis bullosa (RDEB) lack functional type VII collagen owing to mutations in the gene COL7A1 and suffer severe blistering and chronic wounds that ultimately lead to infection and development of lethal squamous cell carcinoma. The discovery of induced pluripotent stem cells (iPSCs) and the ability to edit the genome bring the possibility to provide definitive genetic therapy through corrected autologous tissues. We generated patient-derived COL7A1 -corrected epithelial keratinocyte sheets for autologous grafting. We demonstrate the utility of sequential reprogramming and adenovirus-associated viral genome editing to generate corrected iPSC banks. iPSC-derived keratinocytes were produced with minimal heterogeneity, and these cells secreted wild-type type VII collagen, resulting in stratified epidermis in vitro in organotypic cultures and in vivo in mice. Sequencing of corrected cell lines before tissue formation revealed heterogeneity of cancer-predisposingmutations, allowing us to select COL7A1-corrected banks withminimal mutational burden for downstream epidermis production. Our results provide a clinical platform to use iPSCs in the treatment of debilitating genodermatoses, such as RDEB.
| Original language | English (US) |
|---|---|
| Journal | Science Translational Medicine |
| Volume | 6 |
| Issue number | 264 |
| DOIs | |
| State | Published - Nov 26 2014 |
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ASJC Scopus subject areas
- Medicine(all)
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Human COL7A1-corrected induced pluripotent stem cells for the treatment of recessive dystrophic epidermolysis bullosa. / Sebastiano, Vittorio; Zhen, Hanson Hui; Derafshi, Bahareh Haddad; Bashkirova, Elizaveta; Melo, Sandra P.; Wang, Pei; Leung, Thomas L.; Siprashvili, Zurab; Tichy, Andrea; Li, Jiang; Ameen, Mohammed; Hawkins, John; Lee, Susie; Li, Lingjie; Schwertschkow, Aaron; Bauer, Gerhard; Lisowski, Leszek; Kay, Mark A.; Kim, Seung K.; Lane, Alfred T.; Wernig, Marius; Oro, Anthony E.
In: Science Translational Medicine, Vol. 6, No. 264, 26.11.2014.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Human COL7A1-corrected induced pluripotent stem cells for the treatment of recessive dystrophic epidermolysis bullosa
AU - Sebastiano, Vittorio
AU - Zhen, Hanson Hui
AU - Derafshi, Bahareh Haddad
AU - Bashkirova, Elizaveta
AU - Melo, Sandra P.
AU - Wang, Pei
AU - Leung, Thomas L.
AU - Siprashvili, Zurab
AU - Tichy, Andrea
AU - Li, Jiang
AU - Ameen, Mohammed
AU - Hawkins, John
AU - Lee, Susie
AU - Li, Lingjie
AU - Schwertschkow, Aaron
AU - Bauer, Gerhard
AU - Lisowski, Leszek
AU - Kay, Mark A.
AU - Kim, Seung K.
AU - Lane, Alfred T.
AU - Wernig, Marius
AU - Oro, Anthony E.
PY - 2014/11/26
Y1 - 2014/11/26
N2 - Patients with recessive dystrophic epidermolysis bullosa (RDEB) lack functional type VII collagen owing to mutations in the gene COL7A1 and suffer severe blistering and chronic wounds that ultimately lead to infection and development of lethal squamous cell carcinoma. The discovery of induced pluripotent stem cells (iPSCs) and the ability to edit the genome bring the possibility to provide definitive genetic therapy through corrected autologous tissues. We generated patient-derived COL7A1 -corrected epithelial keratinocyte sheets for autologous grafting. We demonstrate the utility of sequential reprogramming and adenovirus-associated viral genome editing to generate corrected iPSC banks. iPSC-derived keratinocytes were produced with minimal heterogeneity, and these cells secreted wild-type type VII collagen, resulting in stratified epidermis in vitro in organotypic cultures and in vivo in mice. Sequencing of corrected cell lines before tissue formation revealed heterogeneity of cancer-predisposingmutations, allowing us to select COL7A1-corrected banks withminimal mutational burden for downstream epidermis production. Our results provide a clinical platform to use iPSCs in the treatment of debilitating genodermatoses, such as RDEB.
AB - Patients with recessive dystrophic epidermolysis bullosa (RDEB) lack functional type VII collagen owing to mutations in the gene COL7A1 and suffer severe blistering and chronic wounds that ultimately lead to infection and development of lethal squamous cell carcinoma. The discovery of induced pluripotent stem cells (iPSCs) and the ability to edit the genome bring the possibility to provide definitive genetic therapy through corrected autologous tissues. We generated patient-derived COL7A1 -corrected epithelial keratinocyte sheets for autologous grafting. We demonstrate the utility of sequential reprogramming and adenovirus-associated viral genome editing to generate corrected iPSC banks. iPSC-derived keratinocytes were produced with minimal heterogeneity, and these cells secreted wild-type type VII collagen, resulting in stratified epidermis in vitro in organotypic cultures and in vivo in mice. Sequencing of corrected cell lines before tissue formation revealed heterogeneity of cancer-predisposingmutations, allowing us to select COL7A1-corrected banks withminimal mutational burden for downstream epidermis production. Our results provide a clinical platform to use iPSCs in the treatment of debilitating genodermatoses, such as RDEB.
UR - http://www.scopus.com/inward/record.url?scp=84914166169&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84914166169&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.3009540
DO - 10.1126/scitranslmed.3009540
M3 - Article
C2 - 25429056
AN - SCOPUS:84914166169
VL - 6
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 264
ER -