A Aiuti

A Biffi

A Cavazza

A Ciccia

A Lombardo

AE Boitano

Andrea Calabria

Angelo Lombardo

B Gentner

Bernhard Gentner

C Mussolino

Chiara Bonini

CJ Braun

CJ Wu

Claudia Firrito

D Hockemeyer

Davide Moi

DT Harris

DW Barnett

E Provasi

Eugenio Montini

FD Urnov

G Escobar

Giulia Escobar

Giulia Schiroli

H Li

J Mátrai

J Zou

JC Miller

JD Sander

JK Joung

L Gattinoni

L Naldini

Luigi Naldini

M Cavazzana-Calvo

M Milyavsky

M Mohrin

MA Larkin

Michael C. Holmes

Mirjam van der Burg

N Cartier

N Cieri

N Holt

NB Woods

P Tebas

Philip D. Gregory

Pietro Genovese

R Gabriel

Roberta Mazzieri

S Doulatov

S Mukherjee

TE North

Tiziano Di Tomaso

W Goessling

Y Akatsuka

PubMed

Targeted genome editing by artificial nucleases has brought the goal of site-specific transgene integration and gene correction within the reach of gene therapy. However, its application to long-term repopulating haematopoietic stem cells (HSCs) has remained elusive. Here we show that poor permissiveness to gene transfer and limited proficiency of the homology-directed DNA repair pathway constrain gene targeting in human HSCs. By tailoring delivery platforms and culture conditions we overcame these barriers and provide stringent evidence of targeted integration in human HSCs by long-term multilineage repopulation of transplanted mice. We demonstrate the therapeutic potential of our strategy by targeting a corrective complementary DNA into the IL2RG gene of HSCs from healthy donors and a subject with X-linked severe combined immunodeficiency (SCID-X1). Gene-edited HSCs sustained normal haematopoiesis and gave rise to functional lymphoid cells that possess a selective growth advantage over those carrying disruptive IL2RG mutations. These results open up new avenues for treating SCID-X1 and other diseases

Genovese, P

Schiroli, G

Escobar, G

Di Tomaso, T

Firrito, C

Calabria, A

Moi, D

Mazzieri, R

Bonini, C

Holmes, MC

Gregory, PD

van der Burg, Mirjam

Gentner, B

Montini, E

Lombardo, A

Naldini, L

NARCIS 

Targeted genome editing in human repopulating haematopoietic stem cells

Crossref

Nature

EUR Research Repository

Genovese, P. (Pietro)

Schiroli, G. (Giulia)

Escobar, G. (Giulia)

Di Tomaso, T. (Tiziano)

Firrito, C. (Claudia)

Calabria, A. (Andrea)

Moi, D. (Davide)

Mazzieri, R. (Roberta)

Bonini, C. (Chiara)

Holmes, M.V. (Michael)

Gregory, P.D. (Philip)

Burg, M. (Mirjam) van der

Gentner, B. (Bernhard)

Montini, E. (Eugenio)

Lombardo, A. (Angelo)

Naldini, L. (Luigi)

Erasmus University Digital Repository

Genovese, Pietro

Schiroli, Giulia

Escobar, Giulia

Di Tomaso, Tiziano

Firrito, Claudio

Calabria, Andrea

Moi, Davide

Mazzieri, Roberta

Bonini, Chiara

Holmes, Michael C.

Gregory, Philip D.

Gentner, Bernhard

Montini, Eugenio

Lombardo, Angelo

Naldini, Luigi

University of Queensland eSpace

http://www.nature.com/authors/editorial_policies/license.html#terms