Human COL7A1-corrected induced pluripotent stem cells for the treatment of recessive dystrophic epidermolysis bullosa

Vittorio Sebastiano, Hanson Hui Zhen, Bahareh Haddad Derafshi, Elizaveta Bashkirova, Sandra P. Melo, Pei Wang, Thomas L. Leung, Zurab Siprashvili, Andrea Tichy, Jiang Li, Mohammed Ameen, John Hawkins, Susie Lee, Lingjie Li, Aaron Schwertschkow, Gerhard Bauer, Leszek Lisowski, Mark A. Kay, Seung K. Kim, Alfred T. Lane & 2 others Marius Wernig, Anthony E. Oro

Research output: Contribution to journalArticle

90 Citations (Scopus)

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 languageEnglish (US)
JournalScience Translational Medicine
Volume6
Issue number264
DOIs
StatePublished - Nov 26 2014

Fingerprint

Epidermolysis Bullosa Dystrophica
Induced Pluripotent Stem Cells
Collagen Type VII
Keratinocytes
Epidermis
Viral Genome
Therapeutics
Adenoviridae
Genetic Therapy
Squamous Cell Carcinoma
Genome
Cell Line
Mutation
Wounds and Injuries
Infection
Genes
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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 journalArticle

Sebastiano, V, Zhen, HH, Derafshi, BH, Bashkirova, E, Melo, SP, Wang, P, Leung, TL, Siprashvili, Z, Tichy, A, Li, J, Ameen, M, Hawkins, J, Lee, S, Li, L, Schwertschkow, A, Bauer, G, Lisowski, L, Kay, MA, Kim, SK, Lane, AT, Wernig, M & Oro, AE 2014, 'Human COL7A1-corrected induced pluripotent stem cells for the treatment of recessive dystrophic epidermolysis bullosa', Science Translational Medicine, vol. 6, no. 264. https://doi.org/10.1126/scitranslmed.3009540
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. / Human COL7A1-corrected induced pluripotent stem cells for the treatment of recessive dystrophic epidermolysis bullosa. In: Science Translational Medicine. 2014 ; Vol. 6, No. 264.
@article{08d02a6719dc400892305235dea12ee5,
title = "Human COL7A1-corrected induced pluripotent stem cells for the treatment of recessive dystrophic epidermolysis bullosa",
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.",
author = "Vittorio Sebastiano and Zhen, {Hanson Hui} and Derafshi, {Bahareh Haddad} and Elizaveta Bashkirova and Melo, {Sandra P.} and Pei Wang and Leung, {Thomas L.} and Zurab Siprashvili and Andrea Tichy and Jiang Li and Mohammed Ameen and John Hawkins and Susie Lee and Lingjie Li and Aaron Schwertschkow and Gerhard Bauer and Leszek Lisowski and Kay, {Mark A.} and Kim, {Seung K.} and Lane, {Alfred T.} and Marius Wernig and Oro, {Anthony E.}",
year = "2014",
month = "11",
day = "26",
doi = "10.1126/scitranslmed.3009540",
language = "English (US)",
volume = "6",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "264",

}

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

VL - 6

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 264

ER -