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Lentivirus-based Gene Therapy of Hematopoietic Stem Cells in Wiskott-Aldrich Syndrome
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...
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| Published in: | Science (American Association for the Advancement of Science) 2013-07, Vol.341 (6148), p.1233151-1233151 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| container_end_page | 1233151 |
| container_issue | 6148 |
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| container_title | Science (American Association for the Advancement of Science) |
| container_volume | 341 |
| creator | 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 Orange, Jordan Galimberti, Stefania Valsecchi, Maria Grazia Biffi, Alessandra Montini, Eugenio Villa, Anna Ciceri, Fabio Roncarolo, Maria Grazia Naldini, Luigi |
| description | 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 re-infused the cells after reduced-intensity conditioning regimen. All three patients showed stable engraftment of WASP-expressing cells and improvements in platelet counts, immune functions, and clinical score. Vector integration analyses revealed highly polyclonal and multi-lineage 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 20–32 months. Although extended clinical observation is required to establish long-term safety, lentiviral gene therapy represents a promising treatment for WAS. |
| doi_str_mv | 10.1126/science.1233151 |
| format | article |
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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 re-infused the cells after reduced-intensity conditioning regimen. All three patients showed stable engraftment of WASP-expressing cells and improvements in platelet counts, immune functions, and clinical score. Vector integration analyses revealed highly polyclonal and multi-lineage 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 20–32 months. 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Jordan</creatorcontrib><creatorcontrib>Galimberti, Stefania</creatorcontrib><creatorcontrib>Valsecchi, Maria Grazia</creatorcontrib><creatorcontrib>Biffi, Alessandra</creatorcontrib><creatorcontrib>Montini, Eugenio</creatorcontrib><creatorcontrib>Villa, Anna</creatorcontrib><creatorcontrib>Ciceri, Fabio</creatorcontrib><creatorcontrib>Roncarolo, Maria Grazia</creatorcontrib><creatorcontrib>Naldini, Luigi</creatorcontrib><collection>PubMed Central (Full Participant titles)</collection><jtitle>Science (American Association for the Advancement of Science)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Aiuti, Alessandro</au><au>Biasco, Luca</au><au>Scaramuzza, Samantha</au><au>Ferrua, Francesca</au><au>Cicalese, Maria Pia</au><au>Baricordi, Cristina</au><au>Dionisio, Francesca</au><au>Calabria, Andrea</au><au>Giannelli, Stefania</au><au>Castiello, Maria Carmina</au><au>Bosticardo, Marita</au><au>Evangelio, Costanza</au><au>Assanelli, Andrea</au><au>Casiraghi, Miriam</au><au>Di Nunzio, Sara</au><au>Callegaro, Luciano</au><au>Benati, Claudia</au><au>Rizzardi, Paolo</au><au>Pellin, Danilo</au><au>Di Serio, Clelia</au><au>Schmidt, Manfred</au><au>Von Kalle, Christof</au><au>Gardner, Jason</au><au>Mehta, Nalini</au><au>Neduva, Victor</au><au>Dow, David J.</au><au>Galy, Anne</au><au>Miniero, Roberto</au><au>Finocchi, Andrea</au><au>Metin, Ayse</au><au>Banerjee, Pinaki</au><au>Orange, Jordan</au><au>Galimberti, Stefania</au><au>Valsecchi, Maria Grazia</au><au>Biffi, Alessandra</au><au>Montini, Eugenio</au><au>Villa, Anna</au><au>Ciceri, Fabio</au><au>Roncarolo, Maria Grazia</au><au>Naldini, Luigi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Lentivirus-based Gene Therapy of Hematopoietic Stem Cells in Wiskott-Aldrich Syndrome</atitle><jtitle>Science (American Association for the Advancement of Science)</jtitle><date>2013-07-11</date><risdate>2013</risdate><volume>341</volume><issue>6148</issue><spage>1233151</spage><epage>1233151</epage><pages>1233151-1233151</pages><issn>0036-8075</issn><eissn>1095-9203</eissn><notes>These authors contributed equally to this work</notes><notes>Equal second author contribution</notes><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 re-infused the cells after reduced-intensity conditioning regimen. All three patients showed stable engraftment of WASP-expressing cells and improvements in platelet counts, immune functions, and clinical score. Vector integration analyses revealed highly polyclonal and multi-lineage 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 20–32 months. Although extended clinical observation is required to establish long-term safety, lentiviral gene therapy represents a promising treatment for WAS.</abstract><pmid>23845947</pmid><doi>10.1126/science.1233151</doi></addata></record> |
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| title | Lentivirus-based Gene Therapy of Hematopoietic Stem Cells in Wiskott-Aldrich Syndrome |
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