Giuseppe
Emeritus
[Source: Science, full page: (LINK). Abstract, edited. h / t #fattoquotidiano ]
<CITE>Published Online July 11 2013</CITE>
<CITE></CITE>
<CITE>Science DOI: 10.1126/science.1233158 </CITE>
<CITE></CITE>
<CITE></CITE>Research Article
Lentiviral Hematopoietic Stem Cell Gene Therapy Benefits Metachromatic Leukodystrophy
Alessandra Biffi<SUP>1</SUP>,<SUP>2</SUP>,<SUP>3</SUP>,*,?, Eugenio Montini<SUP>1</SUP>,*, Laura Lorioli<SUP>1</SUP>,<SUP>2</SUP>,<SUP>3</SUP>,<SUP>4</SUP>, Martina Cesani<SUP>1</SUP>, Francesca Fumagalli<SUP>2</SUP>,<SUP>4</SUP>,<SUP>5</SUP>, Tiziana Plati<SUP>1</SUP>, Cristina Baldoli<SUP>6</SUP>, Sabata Martino<SUP>7</SUP>, Andrea Calabria<SUP>1</SUP>, Sabrina Canale<SUP>2</SUP>, Fabrizio Benedicenti<SUP>1</SUP>, Giuliana Vallanti<SUP>8</SUP>, Luca Biasco<SUP>1</SUP>, Simone Leo<SUP>9</SUP>, Nabil Kabbara<SUP>10</SUP>, Gianluigi Zanetti<SUP>9</SUP>, William B. Rizzo<SUP>11</SUP>, Nalini A. L. Mehta<SUP>12</SUP>, Maria Pia Cicalese<SUP>2</SUP>,<SUP>3</SUP>, Miriam Casiraghi<SUP>2</SUP>, Jaap J. Boelens<SUP>13</SUP>, Ubaldo Del Carro<SUP>5</SUP>, David J. Dow<SUP>12</SUP>, Manfred Schmidt<SUP>14</SUP>, Andrea Assanelli<SUP>3</SUP>,<SUP>15</SUP>, Victor Neduva<SUP>12</SUP>, Clelia Di Serio<SUP>4</SUP>, Elia Stupka<SUP>16</SUP>, Jason Gardner<SUP>17</SUP>, Christof von Kalle<SUP>14</SUP>, Claudio Bordignon<SUP>4</SUP>,<SUP>8</SUP>, Fabio Ciceri<SUP>3</SUP>,<SUP>15</SUP>, Attilio Rovelli<SUP>18</SUP>, Maria Grazia Roncarolo<SUP>1</SUP>,<SUP>2</SUP>,<SUP>3</SUP>,<SUP>4</SUP>, Alessandro Aiuti<SUP>1</SUP>,<SUP>2</SUP>,<SUP>3</SUP>,<SUP>19</SUP>, Maria Sessa<SUP>2</SUP>,<SUP>5</SUP>, Luigi Naldini<SUP>1</SUP>,<SUP>4</SUP>,?
Author Affiliations: <SUP>1</SUP>San Raffaele Telethon Institute for Gene Therapy (TIGET), San Raffaele Scientific Institute, 20132 Milan, Italy. <SUP>2</SUP>TIGET Pediatric Clinical Research Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy. <SUP>3</SUP>Pediatric Immunohematology and Bone Marrow Transplant Unit, San Raffaele Scientific Institute, 20132 Milan, Italy. <SUP>4</SUP>Vita-Salute San Raffaele University, 20132 Milan, Italy. <SUP>5</SUP>Neurology Unit, Department of Neurology, San Raffaele Scientific Institute, 20132 Milan, Italy. <SUP>6</SUP>Neuroradiology Unit, Head and Neck Department, San Raffaele Scientific Institute, 20132 Milan, Italy. <SUP>7</SUP>Department of Experimental Medicine and Biochemical Sciences, University of Perugia, 06122 Perugia, Italy. <SUP>8</SUP>MolMed S.p.A., 20132 Milan, Italy. <SUP>9</SUP>Distributed Computing Group, Center for Advanced Studies, Research and Development in Sardinia (CRS4), 09010 Pula, Italy. <SUP>10</SUP>Pediatric Hematology Oncology Division, Rafic Hariri University Hospital, Beirut, Lebanon. <SUP>11</SUP>Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE 68198, USA. <SUP>12</SUP>Molecular and Cellular Technologies, GlaxoSmithKline, Stevenage 5G1 2NY, UK. <SUP>13</SUP>Pediatric Blood and Marrow Transplantation Program, University Medical Center 3584 CX Utrecht, Netherlands. <SUP>14</SUP>Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, 69120 Heidelberg, Germany. <SUP>15</SUP>Hematology and Bone Marrow Transplant Unit, San Raffaele Scientific Institute, 20132 Milan, Italy. <SUP>16</SUP>Center for Translational Genomics and BioInformatics, San Raffaele Scientific Institute, 20132 Milan, Italy. <SUP>17</SUP>Regenerative Medicine Discovery Performance Unit, GlaxoSmithKline Research and Development, King of Prussia, PA 19406, USA. <SUP>18</SUP>Bone Marrow Transplant Unit, MBBM Foundation, Pediatric Department, Milano-Bicocca University at San Gerardo Hospital, 20052 Monza, Italy. <SUP>19</SUP>University of Rome Tor Vergata, 00133 Rome, Italy.
?To whom correspondence should be addressed. E-mail: biffi.alessandra@hsr.it (A.B.); naldini.luigi@hsr.it (L.N.)
* These authors contributed equally to this work.
Abstract
Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disease caused by arylsulfatase A (ARSA) deficiency. Patients with MLD exhibit progressive motor and cognitive impairment and die within few years of symptom onset. We used a lentiviral vector to transfer a functional ARSA gene into hematopoietic stem cells (HSCs) from three presymptomatic patients who showed genetic, biochemical, and neurophysiological evidence of late infantile MLD. After reinfusion of the gene-corrected HSCs, the patients showed extensive and stable ARSA gene replacement, which led to high enzyme expression throughout hematopoietic lineages and in cerebrospinal fluid. Analyses of vector integrations revealed no evidence of aberrant clonal behavior. Notably, the disease did not manifest or progress in the three patients 7 to 21 months beyond the predicted age of symptom onset. These findings indicate that extensive genetic engineering of human hematopoiesis can be achieved with lentiviral vectors and that this approach may offer therapeutic benefit for MLD patients.
Received for publication 26 November 2012. Accepted for publication 25 June 2013.
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<CITE>Published Online July 11 2013</CITE>
<CITE></CITE>
<CITE>Science DOI: 10.1126/science.1233158 </CITE>
<CITE></CITE>
<CITE></CITE>Research Article
Lentiviral Hematopoietic Stem Cell Gene Therapy Benefits Metachromatic Leukodystrophy
Alessandra Biffi<SUP>1</SUP>,<SUP>2</SUP>,<SUP>3</SUP>,*,?, Eugenio Montini<SUP>1</SUP>,*, Laura Lorioli<SUP>1</SUP>,<SUP>2</SUP>,<SUP>3</SUP>,<SUP>4</SUP>, Martina Cesani<SUP>1</SUP>, Francesca Fumagalli<SUP>2</SUP>,<SUP>4</SUP>,<SUP>5</SUP>, Tiziana Plati<SUP>1</SUP>, Cristina Baldoli<SUP>6</SUP>, Sabata Martino<SUP>7</SUP>, Andrea Calabria<SUP>1</SUP>, Sabrina Canale<SUP>2</SUP>, Fabrizio Benedicenti<SUP>1</SUP>, Giuliana Vallanti<SUP>8</SUP>, Luca Biasco<SUP>1</SUP>, Simone Leo<SUP>9</SUP>, Nabil Kabbara<SUP>10</SUP>, Gianluigi Zanetti<SUP>9</SUP>, William B. Rizzo<SUP>11</SUP>, Nalini A. L. Mehta<SUP>12</SUP>, Maria Pia Cicalese<SUP>2</SUP>,<SUP>3</SUP>, Miriam Casiraghi<SUP>2</SUP>, Jaap J. Boelens<SUP>13</SUP>, Ubaldo Del Carro<SUP>5</SUP>, David J. Dow<SUP>12</SUP>, Manfred Schmidt<SUP>14</SUP>, Andrea Assanelli<SUP>3</SUP>,<SUP>15</SUP>, Victor Neduva<SUP>12</SUP>, Clelia Di Serio<SUP>4</SUP>, Elia Stupka<SUP>16</SUP>, Jason Gardner<SUP>17</SUP>, Christof von Kalle<SUP>14</SUP>, Claudio Bordignon<SUP>4</SUP>,<SUP>8</SUP>, Fabio Ciceri<SUP>3</SUP>,<SUP>15</SUP>, Attilio Rovelli<SUP>18</SUP>, Maria Grazia Roncarolo<SUP>1</SUP>,<SUP>2</SUP>,<SUP>3</SUP>,<SUP>4</SUP>, Alessandro Aiuti<SUP>1</SUP>,<SUP>2</SUP>,<SUP>3</SUP>,<SUP>19</SUP>, Maria Sessa<SUP>2</SUP>,<SUP>5</SUP>, Luigi Naldini<SUP>1</SUP>,<SUP>4</SUP>,?
Author Affiliations: <SUP>1</SUP>San Raffaele Telethon Institute for Gene Therapy (TIGET), San Raffaele Scientific Institute, 20132 Milan, Italy. <SUP>2</SUP>TIGET Pediatric Clinical Research Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy. <SUP>3</SUP>Pediatric Immunohematology and Bone Marrow Transplant Unit, San Raffaele Scientific Institute, 20132 Milan, Italy. <SUP>4</SUP>Vita-Salute San Raffaele University, 20132 Milan, Italy. <SUP>5</SUP>Neurology Unit, Department of Neurology, San Raffaele Scientific Institute, 20132 Milan, Italy. <SUP>6</SUP>Neuroradiology Unit, Head and Neck Department, San Raffaele Scientific Institute, 20132 Milan, Italy. <SUP>7</SUP>Department of Experimental Medicine and Biochemical Sciences, University of Perugia, 06122 Perugia, Italy. <SUP>8</SUP>MolMed S.p.A., 20132 Milan, Italy. <SUP>9</SUP>Distributed Computing Group, Center for Advanced Studies, Research and Development in Sardinia (CRS4), 09010 Pula, Italy. <SUP>10</SUP>Pediatric Hematology Oncology Division, Rafic Hariri University Hospital, Beirut, Lebanon. <SUP>11</SUP>Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE 68198, USA. <SUP>12</SUP>Molecular and Cellular Technologies, GlaxoSmithKline, Stevenage 5G1 2NY, UK. <SUP>13</SUP>Pediatric Blood and Marrow Transplantation Program, University Medical Center 3584 CX Utrecht, Netherlands. <SUP>14</SUP>Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, 69120 Heidelberg, Germany. <SUP>15</SUP>Hematology and Bone Marrow Transplant Unit, San Raffaele Scientific Institute, 20132 Milan, Italy. <SUP>16</SUP>Center for Translational Genomics and BioInformatics, San Raffaele Scientific Institute, 20132 Milan, Italy. <SUP>17</SUP>Regenerative Medicine Discovery Performance Unit, GlaxoSmithKline Research and Development, King of Prussia, PA 19406, USA. <SUP>18</SUP>Bone Marrow Transplant Unit, MBBM Foundation, Pediatric Department, Milano-Bicocca University at San Gerardo Hospital, 20052 Monza, Italy. <SUP>19</SUP>University of Rome Tor Vergata, 00133 Rome, Italy.
?To whom correspondence should be addressed. E-mail: biffi.alessandra@hsr.it (A.B.); naldini.luigi@hsr.it (L.N.)
* These authors contributed equally to this work.
Abstract
Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disease caused by arylsulfatase A (ARSA) deficiency. Patients with MLD exhibit progressive motor and cognitive impairment and die within few years of symptom onset. We used a lentiviral vector to transfer a functional ARSA gene into hematopoietic stem cells (HSCs) from three presymptomatic patients who showed genetic, biochemical, and neurophysiological evidence of late infantile MLD. After reinfusion of the gene-corrected HSCs, the patients showed extensive and stable ARSA gene replacement, which led to high enzyme expression throughout hematopoietic lineages and in cerebrospinal fluid. Analyses of vector integrations revealed no evidence of aberrant clonal behavior. Notably, the disease did not manifest or progress in the three patients 7 to 21 months beyond the predicted age of symptom onset. These findings indicate that extensive genetic engineering of human hematopoiesis can be achieved with lentiviral vectors and that this approach may offer therapeutic benefit for MLD patients.
Received for publication 26 November 2012. Accepted for publication 25 June 2013.
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