Lentiviral hematopoietic stem cell gene therapy in patients with wiskott-aldrich syndrome

Alessandro Aiuti; Luca Biasco; Samantha Scaramuzza; Francesca Ferrua; Maria Pia Cicalese; Cristina Baricordi; Francesca Dionisio; Andrea Calabria; Stefania Giannelli; Maria Carmina Castiello; Marita Bosticardo; Costanza Evangelio; Andrea Assanelli; Miriam Casiraghi; Sara Di Nunzio; Luciano Callegaro; Claudia Benati; Paolo Rizzardi; Danilo Pellin; Clelia Di Serio; Manfred Schmidt; Christof Von Kalle; Jason Gardner; Nalini Mehta; Victor Neduva; David J. Dow; Anne Galy; Roberto Miniero; Andrea Finocchi; Ayse Metin; Pinaki P. Banerjee; Jordan S. Orange; Stefania Galimberti; Maria Grazia Valsecchi; Alessandra Biffi; Eugenio Montini; Anna Villa; Fabio Ciceri; Maria Grazia Roncarolo; Luigi Naldini

doi:10.1126/science.1233151

Lentiviral hematopoietic stem cell gene therapy in patients with wiskott-aldrich syndrome

Alessandro Aiuti, Luca Biasco, Samantha Scaramuzza, Francesca Ferrua, Maria Pia Cicalese, Cristina Baricordi, Francesca Dionisio, Andrea Calabria, Stefania Giannelli, Maria Carmina Castiello, Marita Bosticardo, Costanza Evangelio, Andrea Assanelli, Miriam Casiraghi, Sara Di Nunzio, Luciano Callegaro, Claudia Benati, Paolo Rizzardi, Danilo Pellin, Clelia Di SerioManfred Schmidt, Christof Von Kalle, Jason Gardner, Nalini Mehta, Victor Neduva, David J. Dow, Anne Galy, Roberto Miniero, Andrea Finocchi, Ayse Metin, Pinaki P. Banerjee, Jordan S. Orange, Stefania Galimberti, Maria Grazia Valsecchi, Alessandra Biffi, Eugenio Montini, Anna Villa, Fabio Ciceri, Maria Grazia Roncarolo, Luigi Naldini

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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 (US)
Article number	1233151
Journal	Science
Volume	341
Issue number	6148
DOIs	https://doi.org/10.1126/science.1233151
State	Published - 2013

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Aiuti, A., Biasco, L., Scaramuzza, S., Ferrua, F., Cicalese, M. P., Baricordi, C., Dionisio, F., Calabria, A., Giannelli, S., Castiello, M. C., Bosticardo, M., Evangelio, C., Assanelli, A., Casiraghi, M., Di Nunzio, S., Callegaro, L., Benati, C., Rizzardi, P., Pellin, D., ... Naldini, L. (2013). Lentiviral hematopoietic stem cell gene therapy in patients with wiskott-aldrich syndrome. Science, 341(6148), Article 1233151. https://doi.org/10.1126/science.1233151

Aiuti, A, Biasco, L, Scaramuzza, S, Ferrua, F, Cicalese, MP, Baricordi, C, Dionisio, F, Calabria, A, Giannelli, S, Castiello, MC, Bosticardo, M, Evangelio, C, Assanelli, A, Casiraghi, M, Di Nunzio, S, Callegaro, L, Benati, C, Rizzardi, P, Pellin, D, Di Serio, C, Schmidt, M, Von Kalle, C, Gardner, J, Mehta, N, Neduva, V, Dow, DJ, Galy, A, Miniero, R, Finocchi, A, Metin, A, Banerjee, PP, Orange, JS, Galimberti, S, Valsecchi, MG, Biffi, A, Montini, E, Villa, A, Ciceri, F, Roncarolo, MG & Naldini, L 2013, 'Lentiviral hematopoietic stem cell gene therapy in patients with wiskott-aldrich syndrome', Science, vol. 341, no. 6148, 1233151. https://doi.org/10.1126/science.1233151

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title = "Lentiviral hematopoietic stem cell gene therapy in patients with wiskott-aldrich syndrome",

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.",

author = "Alessandro Aiuti and Luca Biasco and Samantha Scaramuzza and Francesca Ferrua and Cicalese, {Maria Pia} and Cristina Baricordi and Francesca Dionisio and Andrea Calabria and Stefania Giannelli and Castiello, {Maria Carmina} and Marita Bosticardo and Costanza Evangelio and Andrea Assanelli and Miriam Casiraghi and {Di Nunzio}, Sara and Luciano Callegaro and Claudia Benati and Paolo Rizzardi and Danilo Pellin and {Di Serio}, Clelia and Manfred Schmidt and {Von Kalle}, Christof and Jason Gardner and Nalini Mehta and Victor Neduva and Dow, {David J.} and Anne Galy and Roberto Miniero and Andrea Finocchi and Ayse Metin and Banerjee, {Pinaki P.} and Orange, {Jordan S.} and Stefania Galimberti and Valsecchi, {Maria Grazia} and Alessandra Biffi and Eugenio Montini and Anna Villa and Fabio Ciceri and Roncarolo, {Maria Grazia} and Luigi Naldini",

year = "2013",

doi = "10.1126/science.1233151",

language = "English (US)",

volume = "341",

journal = "Science",

issn = "0036-8075",

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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.

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U2 - 10.1126/science.1233151

DO - 10.1126/science.1233151

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AN - SCOPUS:84879867061

SN - 0036-8075

VL - 341

JO - Science

JF - Science

IS - 6148

M1 - 1233151

ER -

Lentiviral hematopoietic stem cell gene therapy in patients with wiskott-aldrich syndrome

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