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

Research output: Contribution to journalArticle

601 Citations (Scopus)

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 languageEnglish
Article number1233151
JournalScience
Volume341
Issue number6148
DOIs
Publication statusPublished - 2013
Externally publishedYes

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Wiskott-Aldrich Syndrome
Cell- and Tissue-Based Therapy
Hematopoietic Stem Cells
Genetic Therapy
Wiskott-Aldrich Syndrome Protein
Hematopoiesis
Cytoskeleton
Platelet Count
Oncogenes
Genes
Observation
Tissue Donors
Transplants
Safety
Mutation
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Aiuti, A., Biasco, L., Scaramuzza, S., Ferrua, F., Cicalese, M. P., Baricordi, C., ... Naldini, L. (2013). Lentiviral hematopoietic stem cell gene therapy in patients with wiskott-aldrich syndrome. Science, 341(6148), [1233151]. https://doi.org/10.1126/science.1233151

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 journalArticle

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
Aiuti A, Biasco L, Scaramuzza S, Ferrua F, Cicalese MP, Baricordi C et al. Lentiviral hematopoietic stem cell gene therapy in patients with wiskott-aldrich syndrome. Science. 2013;341(6148). 1233151. https://doi.org/10.1126/science.1233151
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. / Lentiviral hematopoietic stem cell gene therapy in patients with wiskott-aldrich syndrome. In: Science. 2013 ; Vol. 341, No. 6148.
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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.",
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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

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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.

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