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Science. Lentiviral Hematopoietic Stem Cell Gene Therapy in Patients with Wiskott-Aldrich Syndrome
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<CITE>Published Online July 11 2013</CITE>
<CITE></CITE>
<CITE>Science DOI: 10.1126/science.1233151 </CITE>
<CITE></CITE>
<CITE></CITE>Research Article
Lentiviral Hematopoietic Stem Cell Gene Therapy in Patients with Wiskott-Aldrich Syndrome
Alessandro Aiuti<SUP>1</SUP>,<SUP>2</SUP>,<SUP>3</SUP>,<SUP>4</SUP>,*, Luca Biasco<SUP>1</SUP>,<SUP>?</SUP>, Samantha Scaramuzza<SUP>1</SUP>,<SUP>?</SUP>, Francesca Ferrua<SUP>2</SUP>,<SUP>3</SUP>,<SUP>5</SUP>, Maria Pia Cicalese<SUP>2</SUP>,<SUP>3</SUP>, Cristina Baricordi<SUP>1</SUP>, Francesca Dionisio<SUP>1</SUP>, Andrea Calabria<SUP>1</SUP>, Stefania Giannelli<SUP>1</SUP>, Maria Carmina Castiello<SUP>1</SUP>,<SUP>5</SUP>, Marita Bosticardo<SUP>1</SUP>, Costanza Evangelio<SUP>2</SUP>,<SUP>3</SUP>, Andrea Assanelli<SUP>3</SUP>,<SUP>6</SUP>, Miriam Casiraghi<SUP>2</SUP>, Sara Di Nunzio<SUP>2</SUP>, Luciano Callegaro<SUP>2</SUP>, Claudia Benati<SUP>7</SUP>, Paolo Rizzardi<SUP>7</SUP>, Danilo Pellin<SUP>8</SUP>, Clelia Di Serio<SUP>8</SUP>, Manfred Schmidt<SUP>9</SUP>, Christof Von Kalle<SUP>9</SUP>, Jason Gardner<SUP>10</SUP>, Nalini Mehta<SUP>11</SUP>, Victor Neduva<SUP>11</SUP>, David J. Dow<SUP>11</SUP>, Anne Galy<SUP>12</SUP>, Roberto Miniero<SUP>13</SUP>, Andrea Finocchi<SUP>4</SUP>, Ayse Metin<SUP>14</SUP>, Pinaki Banerjee<SUP>15</SUP>, Jordan Orange<SUP>15</SUP>, Stefania Galimberti<SUP>16</SUP>, Maria Grazia Valsecchi<SUP>16</SUP>, Alessandra Biffi<SUP>1</SUP>,<SUP>2</SUP>,<SUP>3</SUP>, Eugenio Montini<SUP>1</SUP>, Anna Villa<SUP>1</SUP>,<SUP>17</SUP>, Fabio Ciceri<SUP>3</SUP>,<SUP>6</SUP>, Maria Grazia Roncarolo<SUP>1</SUP>,<SUP>2</SUP>,<SUP>3</SUP>,<SUP>5</SUP>,<SUP>?</SUP>, Luigi Naldini<SUP>1</SUP>,<SUP>5</SUP>,<SUP>?</SUP>
Author Affiliations : <SUP>1</SUP>San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy. <SUP>2</SUP>HSR-TIGET Pediatric Clinical Research Unit. <SUP>3</SUP>Pediatric Immunohematology and Bone Marrow Transplant Unit, San Raffaele Scientific Institute, Milan, Italy. <SUP>4</SUP>DPUO, University Department of Pediatrics, Bambino Ges? Children?s Hospital and Tor Vergata University, School of Medicine, Rome. <SUP>5</SUP>Vita-Salute San Raffaele University, Milan, Italy. <SUP>6</SUP>Hematology and Bone Marrow Transplant Unit, San Raffaele Scientific Institute, Milan, Italy. <SUP>7</SUP>MolMed SpA, Milan, Italy. <SUP>8</SUP>CUSSB, University Centre of Statistics in the Biomedical Sciences, Vita-Salute San Raffaele University, Milan, Italy. <SUP>9</SUP>Nationales Zentrum f?r Tumorerkrankungen (NCT), Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany. <SUP>10</SUP>Regenerative Medicine Discovery Performance Unit, GlaxoSmithKline Research and Development, King of Prussia, USA. <SUP>11</SUP>Molecular and Cellular Technologies, GlaxoSmithKline, Stevenage, UK. <SUP>12</SUP>UMR 951 ?Molecular Immunology and Biotherapies? Genethon, Evry, France. <SUP>13</SUP>Dipartimento di Scienze Mediche e Chirurgiche, Universit? MAGNA GRAECIA di Catanzaro, Catanzaro, Italy. <SUP>14</SUP>Ankara Dispaki Children?s Hospital, Ankara, Turkey. <SUP>15</SUP>Texas Children's Hospital, Baylor College of Medicine, USA. <SUP>16</SUP>Dip. di Medicina Clinica e Prevenzione, University of Milano-Bicocca, Monza, Italy. <SUP>17</SUP>IRGB-CNR, Milan, Italy.
*Corresponding author. E-mail: aiuti.alessandro@hsr.it
? These authors contributed equally to this work.
? These authors contributed equally to this work.
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 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 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.
Received for publication 26 November 2012. Accepted for publication 24 June 2013.
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<CITE>Published Online July 11 2013</CITE>
<CITE></CITE>
<CITE>Science DOI: 10.1126/science.1233151 </CITE>
<CITE></CITE>
<CITE></CITE>Research Article
Lentiviral Hematopoietic Stem Cell Gene Therapy in Patients with Wiskott-Aldrich Syndrome
Alessandro Aiuti<SUP>1</SUP>,<SUP>2</SUP>,<SUP>3</SUP>,<SUP>4</SUP>,*, Luca Biasco<SUP>1</SUP>,<SUP>?</SUP>, Samantha Scaramuzza<SUP>1</SUP>,<SUP>?</SUP>, Francesca Ferrua<SUP>2</SUP>,<SUP>3</SUP>,<SUP>5</SUP>, Maria Pia Cicalese<SUP>2</SUP>,<SUP>3</SUP>, Cristina Baricordi<SUP>1</SUP>, Francesca Dionisio<SUP>1</SUP>, Andrea Calabria<SUP>1</SUP>, Stefania Giannelli<SUP>1</SUP>, Maria Carmina Castiello<SUP>1</SUP>,<SUP>5</SUP>, Marita Bosticardo<SUP>1</SUP>, Costanza Evangelio<SUP>2</SUP>,<SUP>3</SUP>, Andrea Assanelli<SUP>3</SUP>,<SUP>6</SUP>, Miriam Casiraghi<SUP>2</SUP>, Sara Di Nunzio<SUP>2</SUP>, Luciano Callegaro<SUP>2</SUP>, Claudia Benati<SUP>7</SUP>, Paolo Rizzardi<SUP>7</SUP>, Danilo Pellin<SUP>8</SUP>, Clelia Di Serio<SUP>8</SUP>, Manfred Schmidt<SUP>9</SUP>, Christof Von Kalle<SUP>9</SUP>, Jason Gardner<SUP>10</SUP>, Nalini Mehta<SUP>11</SUP>, Victor Neduva<SUP>11</SUP>, David J. Dow<SUP>11</SUP>, Anne Galy<SUP>12</SUP>, Roberto Miniero<SUP>13</SUP>, Andrea Finocchi<SUP>4</SUP>, Ayse Metin<SUP>14</SUP>, Pinaki Banerjee<SUP>15</SUP>, Jordan Orange<SUP>15</SUP>, Stefania Galimberti<SUP>16</SUP>, Maria Grazia Valsecchi<SUP>16</SUP>, Alessandra Biffi<SUP>1</SUP>,<SUP>2</SUP>,<SUP>3</SUP>, Eugenio Montini<SUP>1</SUP>, Anna Villa<SUP>1</SUP>,<SUP>17</SUP>, Fabio Ciceri<SUP>3</SUP>,<SUP>6</SUP>, Maria Grazia Roncarolo<SUP>1</SUP>,<SUP>2</SUP>,<SUP>3</SUP>,<SUP>5</SUP>,<SUP>?</SUP>, Luigi Naldini<SUP>1</SUP>,<SUP>5</SUP>,<SUP>?</SUP>
Author Affiliations : <SUP>1</SUP>San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy. <SUP>2</SUP>HSR-TIGET Pediatric Clinical Research Unit. <SUP>3</SUP>Pediatric Immunohematology and Bone Marrow Transplant Unit, San Raffaele Scientific Institute, Milan, Italy. <SUP>4</SUP>DPUO, University Department of Pediatrics, Bambino Ges? Children?s Hospital and Tor Vergata University, School of Medicine, Rome. <SUP>5</SUP>Vita-Salute San Raffaele University, Milan, Italy. <SUP>6</SUP>Hematology and Bone Marrow Transplant Unit, San Raffaele Scientific Institute, Milan, Italy. <SUP>7</SUP>MolMed SpA, Milan, Italy. <SUP>8</SUP>CUSSB, University Centre of Statistics in the Biomedical Sciences, Vita-Salute San Raffaele University, Milan, Italy. <SUP>9</SUP>Nationales Zentrum f?r Tumorerkrankungen (NCT), Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany. <SUP>10</SUP>Regenerative Medicine Discovery Performance Unit, GlaxoSmithKline Research and Development, King of Prussia, USA. <SUP>11</SUP>Molecular and Cellular Technologies, GlaxoSmithKline, Stevenage, UK. <SUP>12</SUP>UMR 951 ?Molecular Immunology and Biotherapies? Genethon, Evry, France. <SUP>13</SUP>Dipartimento di Scienze Mediche e Chirurgiche, Universit? MAGNA GRAECIA di Catanzaro, Catanzaro, Italy. <SUP>14</SUP>Ankara Dispaki Children?s Hospital, Ankara, Turkey. <SUP>15</SUP>Texas Children's Hospital, Baylor College of Medicine, USA. <SUP>16</SUP>Dip. di Medicina Clinica e Prevenzione, University of Milano-Bicocca, Monza, Italy. <SUP>17</SUP>IRGB-CNR, Milan, Italy.
*Corresponding author. E-mail: aiuti.alessandro@hsr.it
? These authors contributed equally to this work.
? These authors contributed equally to this work.
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 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 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.
Received for publication 26 November 2012. Accepted for publication 24 June 2013.
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