Lentiviral Hematopoietic Stem Cell Gene Therapy Benefits Metachromatic Leukodystrophy
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- Alessandra Biffi
- San Raffaele Telethon Institute for Gene Therapy (TIGET), San Raffaele Scientific Institute, 20132 Milan, Italy.
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- Eugenio Montini
- San Raffaele Telethon Institute for Gene Therapy (TIGET), San Raffaele Scientific Institute, 20132 Milan, Italy.
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- Laura Lorioli
- San Raffaele Telethon Institute for Gene Therapy (TIGET), San Raffaele Scientific Institute, 20132 Milan, Italy.
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- Martina Cesani
- San Raffaele Telethon Institute for Gene Therapy (TIGET), San Raffaele Scientific Institute, 20132 Milan, Italy.
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- Francesca Fumagalli
- TIGET Pediatric Clinical Research Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy.
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- Tiziana Plati
- San Raffaele Telethon Institute for Gene Therapy (TIGET), San Raffaele Scientific Institute, 20132 Milan, Italy.
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- Cristina Baldoli
- Neuroradiology Unit, Head and Neck Department, San Raffaele Scientific Institute, 20132 Milan, Italy.
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- Sabata Martino
- Department of Experimental Medicine and Biochemical Sciences, University of Perugia, 06122 Perugia, Italy.
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- Andrea Calabria
- San Raffaele Telethon Institute for Gene Therapy (TIGET), San Raffaele Scientific Institute, 20132 Milan, Italy.
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- Sabrina Canale
- TIGET Pediatric Clinical Research Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy.
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- Fabrizio Benedicenti
- San Raffaele Telethon Institute for Gene Therapy (TIGET), San Raffaele Scientific Institute, 20132 Milan, Italy.
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- Giuliana Vallanti
- MolMed, 20132 Milan, Italy.
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- Luca Biasco
- San Raffaele Telethon Institute for Gene Therapy (TIGET), San Raffaele Scientific Institute, 20132 Milan, Italy.
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- Simone Leo
- Distributed Computing Group, Center for Advanced Studies, Research and Development in Sardinia (CRS4), 09010 Pula, Italy.
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- Nabil Kabbara
- Pediatric Hematology Oncology Division, Rafic Hariri University Hospital, Beirut, Lebanon.
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- Gianluigi Zanetti
- Distributed Computing Group, Center for Advanced Studies, Research and Development in Sardinia (CRS4), 09010 Pula, Italy.
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- William B. Rizzo
- Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE 68198, USA.
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- Nalini A. L. Mehta
- Molecular and Cellular Technologies, GlaxoSmithKline, Stevenage 5G1 2NY, UK.
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- Maria Pia Cicalese
- TIGET Pediatric Clinical Research Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy.
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- Miriam Casiraghi
- TIGET Pediatric Clinical Research Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy.
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- Jaap J. Boelens
- Pediatric Blood and Marrow Transplantation Program, University Medical Center 3584 CX Utrecht, Netherlands.
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- Ubaldo Del Carro
- Neurology Unit, Department of Neurology, San Raffaele Scientific Institute, 20132 Milan, Italy.
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- David J. Dow
- Molecular and Cellular Technologies, GlaxoSmithKline, Stevenage 5G1 2NY, UK.
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- Manfred Schmidt
- Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, 69120 Heidelberg, Germany.
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- Andrea Assanelli
- Pediatric Immunohematology and Bone Marrow Transplant Unit, San Raffaele Scientific Institute, 20132 Milan, Italy.
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- Victor Neduva
- Molecular and Cellular Technologies, GlaxoSmithKline, Stevenage 5G1 2NY, UK.
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- Clelia Di Serio
- Vita-Salute San Raffaele University, 20132 Milan, Italy.
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- Elia Stupka
- Center for Translational Genomics and BioInformatics, San Raffaele Scientific Institute, 20132 Milan, Italy.
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- Jason Gardner
- Regenerative Medicine Discovery Performance Unit, GlaxoSmithKline Research and Development, King of Prussia, PA 19406, USA.
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- Christof von Kalle
- Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, 69120 Heidelberg, Germany.
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- Claudio Bordignon
- Vita-Salute San Raffaele University, 20132 Milan, Italy.
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- Fabio Ciceri
- Pediatric Immunohematology and Bone Marrow Transplant Unit, San Raffaele Scientific Institute, 20132 Milan, Italy.
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- Attilio Rovelli
- Bone Marrow Transplant Unit, MBBM Foundation, Pediatric Department, Milano-Bicocca University at San Gerardo Hospital, 20052 Monza, Italy.
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- Maria Grazia Roncarolo
- San Raffaele Telethon Institute for Gene Therapy (TIGET), San Raffaele Scientific Institute, 20132 Milan, Italy.
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- Alessandro Aiuti
- San Raffaele Telethon Institute for Gene Therapy (TIGET), San Raffaele Scientific Institute, 20132 Milan, Italy.
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- Maria Sessa
- TIGET Pediatric Clinical Research Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy.
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- Luigi Naldini
- San Raffaele Telethon Institute for Gene Therapy (TIGET), San Raffaele Scientific Institute, 20132 Milan, Italy.
説明
<jats:title>Next-Generation Gene Therapy</jats:title> <jats:p> Few disciplines in contemporary clinical research have experienced the high expectations directed at the gene therapy field. However, gene therapy has been challenging to translate to the clinic, often because the therapeutic gene is expressed at insufficient levels in the patient or because the gene delivery vector integrates near protooncogenes, which can cause leukemia (see the Perspective by <jats:bold> <jats:related-article xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" issue="6148" page="853" related-article-type="in-this-issue" vol="341" xlink:href="10.1126/science.1242551">Verma</jats:related-article> </jats:bold> ). <jats:bold> Biffi <jats:italic>et al.</jats:italic> </jats:bold> ( <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.sciencemag.org/content/341/6148/1233158.full">1233158</jats:ext-link> , published online 11 July) and <jats:bold> Aiuti <jats:italic>et al.</jats:italic> </jats:bold> ( <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.sciencemag.org/content/341/6148/1233151.full">1233151</jats:ext-link> ; published online 11 July) report progress on both fronts in gene therapy trials of three patients with metachromatic leukodystrophy (MLD), a neurodegenerative disorder, and three patients with Wiskott-Aldrich syndrome (WAS), an immunodeficiency disorder. Optimized lentiviral vectors were used to introduce functional <jats:italic>MLD</jats:italic> or <jats:italic>WAS</jats:italic> genes into the patients' hematopoietic stem cells (HSCs) ex vivo, and the transduced cells were then infused back into the patients, who were then monitored for up to 2 years. In both trials, the patients showed stable engraftment of the transduced HSC and high expression levels of functional <jats:italic>MLD</jats:italic> or <jats:italic>WAS</jats:italic> genes. Encouragingly, there was no evidence of lentiviral vector integration near proto-oncogenes, and the gene therapy treatment halted disease progression in most patients. A longer follow-up period will be needed to further validate efficacy and safety. </jats:p>
収録刊行物
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- Science
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Science 341 (6148), 1233158-, 2013-08-23
American Association for the Advancement of Science (AAAS)