Abstract
Wiskott-Aldrich syndrome (WAS) is an inherited immunodeficiency caused by mutations in the gene encoding WASP, a protein regulating the cytoskeleton. Hematopoietic stem/progenitor cell (HSPC) transplants can be curative, but, when matched donors are unavailable, infusion of autologous HSPCs modified ex vivo by gene therapy is an alternative approach. We used a lentiviral vector encoding functional WASP to genetically correct HSPCs from three WAS patients and reinfused the cells after a reduced-intensity conditioning regimen. All three patients showed stable engraftment of WASP-expressing cells and improvements in platelet counts, immune functions, and clinical scores. Vector integration analyses revealed highly polyclonal and multilineage haematopoiesis resulting from the gene-corrected HSPCs. Lentiviral gene therapy did not induce selection of integrations near oncogenes, and no aberrant clonal expansion was observed after 20 to 32 months. Although extended clinical observation is required to establish long-term safety, lentiviral gene therapy represents a promising treatment for WAS.
| Original language | English |
|---|---|
| Article number | 1233151 |
| Journal | Science |
| Volume | 341 |
| Issue number | 6148 |
| DOIs | |
| Publication status | Published - 2013 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Medicine(all)
- General
Cite this
Lentiviral hematopoietic stem cell gene therapy in patients with wiskott-aldrich syndrome. / Aiuti, Alessandro; Biasco, Luca; Scaramuzza, Samantha; Ferrua, Francesca; Cicalese, Maria Pia; Baricordi, Cristina; Dionisio, Francesca; Calabria, Andrea; Giannelli, Stefania; Castiello, Maria Carmina; Bosticardo, Marita; Evangelio, Costanza; Assanelli, Andrea; Casiraghi, Miriam; Di Nunzio, Sara; Callegaro, Luciano; Benati, Claudia; Rizzardi, Paolo; Pellin, Danilo; Di Serio, Clelia; Schmidt, Manfred; Von Kalle, Christof; Gardner, Jason; Mehta, Nalini; Neduva, Victor; Dow, David J.; Galy, Anne; Miniero, Roberto; Finocchi, Andrea; Metin, Ayse; Banerjee, Pinaki P.; Orange, Jordan S.; Galimberti, Stefania; Valsecchi, Maria Grazia; Biffi, Alessandra; Montini, Eugenio; Villa, Anna; Ciceri, Fabio; Roncarolo, Maria Grazia; Naldini, Luigi.
In: Science, Vol. 341, No. 6148, 1233151, 2013.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Lentiviral hematopoietic stem cell gene therapy in patients with wiskott-aldrich syndrome
AU - Aiuti, Alessandro
AU - Biasco, Luca
AU - Scaramuzza, Samantha
AU - Ferrua, Francesca
AU - Cicalese, Maria Pia
AU - Baricordi, Cristina
AU - Dionisio, Francesca
AU - Calabria, Andrea
AU - Giannelli, Stefania
AU - Castiello, Maria Carmina
AU - Bosticardo, Marita
AU - Evangelio, Costanza
AU - Assanelli, Andrea
AU - Casiraghi, Miriam
AU - Di Nunzio, Sara
AU - Callegaro, Luciano
AU - Benati, Claudia
AU - Rizzardi, Paolo
AU - Pellin, Danilo
AU - Di Serio, Clelia
AU - Schmidt, Manfred
AU - Von Kalle, Christof
AU - Gardner, Jason
AU - Mehta, Nalini
AU - Neduva, Victor
AU - Dow, David J.
AU - Galy, Anne
AU - Miniero, Roberto
AU - Finocchi, Andrea
AU - Metin, Ayse
AU - Banerjee, Pinaki P.
AU - Orange, Jordan S.
AU - Galimberti, Stefania
AU - Valsecchi, Maria Grazia
AU - Biffi, Alessandra
AU - Montini, Eugenio
AU - Villa, Anna
AU - Ciceri, Fabio
AU - Roncarolo, Maria Grazia
AU - Naldini, Luigi
PY - 2013
Y1 - 2013
N2 - Wiskott-Aldrich syndrome (WAS) is an inherited immunodeficiency caused by mutations in the gene encoding WASP, a protein regulating the cytoskeleton. Hematopoietic stem/progenitor cell (HSPC) transplants can be curative, but, when matched donors are unavailable, infusion of autologous HSPCs modified ex vivo by gene therapy is an alternative approach. We used a lentiviral vector encoding functional WASP to genetically correct HSPCs from three WAS patients and reinfused the cells after a reduced-intensity conditioning regimen. All three patients showed stable engraftment of WASP-expressing cells and improvements in platelet counts, immune functions, and clinical scores. Vector integration analyses revealed highly polyclonal and multilineage haematopoiesis resulting from the gene-corrected HSPCs. Lentiviral gene therapy did not induce selection of integrations near oncogenes, and no aberrant clonal expansion was observed after 20 to 32 months. Although extended clinical observation is required to establish long-term safety, lentiviral gene therapy represents a promising treatment for WAS.
AB - Wiskott-Aldrich syndrome (WAS) is an inherited immunodeficiency caused by mutations in the gene encoding WASP, a protein regulating the cytoskeleton. Hematopoietic stem/progenitor cell (HSPC) transplants can be curative, but, when matched donors are unavailable, infusion of autologous HSPCs modified ex vivo by gene therapy is an alternative approach. We used a lentiviral vector encoding functional WASP to genetically correct HSPCs from three WAS patients and reinfused the cells after a reduced-intensity conditioning regimen. All three patients showed stable engraftment of WASP-expressing cells and improvements in platelet counts, immune functions, and clinical scores. Vector integration analyses revealed highly polyclonal and multilineage haematopoiesis resulting from the gene-corrected HSPCs. Lentiviral gene therapy did not induce selection of integrations near oncogenes, and no aberrant clonal expansion was observed after 20 to 32 months. Although extended clinical observation is required to establish long-term safety, lentiviral gene therapy represents a promising treatment for WAS.
UR - http://www.scopus.com/inward/record.url?scp=84879867061&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84879867061&partnerID=8YFLogxK
U2 - 10.1126/science.1233151
DO - 10.1126/science.1233151
M3 - Article
VL - 341
JO - Science
JF - Science
SN - 0036-8075
IS - 6148
M1 - 1233151
ER -