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Cited by 1,025Virus-based gene therapy researchCAR-T cell therapy researchLysosomal Storage Disorders Research

Lentiviral Hematopoietic Stem Cell Gene Therapy in Patients with Wiskott-Aldrich Syndrome

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Aiuti, Alessandro, Biasco, Luca, Scaramuzza, Samantha, Ferrua, Francesca, Cicalese, Maria Pia, Baricordi, Cristina, Dionisio, Francesca, Calabria, Andrea +32 more·2013·Science
DOI 10.1126/science.1233151PMC PMC4375961
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Abstract

Next-Generation Gene Therapy: 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 Verma ). Biffi et al. ( 1233158 , published online 11 July) and Aiuti et al. ( 1233151 ; 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 MLD or WAS 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 MLD or WAS 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.

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Authors
Aiuti, A., Biasco, L., Scaramuzza, S., Ferrua, F., Cicalese, M. P., Baricordi, C., Dionisio, F., Calabria, A., Giannelli, S., Castiello, M. C., 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, D. J., Galy, A., Miniero, R., Finocchi, A., Metin, A., Banerjee, P. P., Orange, J. S., Galimberti, S., Valsecchi, M. G., Biffi, A., Montini, E., Villa, A., Ciceri, F., Roncarolo, M. G., & Naldini, L.
Affiliations
  • University of Rome Tor Vergata (IT)
  • The San Raffaele Telethon Institute for Gene Therapy (IT)
  • Vita-Salute San Raffaele University (IT)
  • IRCCS Ospedale San Raffaele (IT)
  • HSR-TIGET Pediatric Clinical Research Unit, San Raffaele Scientific Institute, 20132 Milan, Italy.
  • MolMed (Italy) (IT)
  • University Centre of Statistics in the Biomedical Sciences (CUSSB), Vita-Salute San Raffaele University, 20132 Milan, Italy.
  • German Cancer Research Center (DE)
  • Nationales Zentrum für Tumorerkrankungen (NCT), Deutsches Krebsforschungszentrum (DKFZ), 69120 Heidelberg, Germany.
  • GlaxoSmithKline (United States) (US)
  • GlaxoSmithKline (United Kingdom) (GB)
  • Genethon (France) (FR)
  • Magna Graecia University (IT)
  • Ankara Children’s Hospital, 06050 Ankara, Turkey.
  • Baylor College of Medicine (US)
  • University of Milano-Bicocca (IT)
  • Institute of Genetic and Biomedical Research (IT)
Corresponding author
  • Aiuti, Alessandro
  • Biasco, Luca
  • Scaramuzza, Samantha
  • Roncarolo, Maria Grazia
  • Naldini, Luigi
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2013-08-23
Volume
341
Issue
6148
Pages
1233151-1233151
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
DOI
10.1126/science.1233151
PMC
PMC4375961
OpenAlex
W2142159826
Cited by
1,025
References
3
Citations by year
2026: 24 · 2025: 21 · 2024: 44 · 2023: 51 · 2022: 62 · 2021: 67 · 2020: 74 · 2019: 89 · 2018: 86 · 2017: 118 · 2016: 121 · 2015: 114 · 2014: 120 · 2013: 30 · 2012: 1
FWCI
73.91
Type
journal article
Language
en
Open access
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion, cc-by-nc-nd)
  • HAL (submittedVersion)
  • BOA (University of Milano-Bicocca) (submittedVersion)
  • Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
  • Padua Research Archive (University of Padova) (submittedVersion)
Funders
  • European Commission (222878, 261387)
  • Fondazione Telethon
  • Ministero della Salute (RF-2009-1485896)
  • National Institute of Allergy and Infectious Diseases (R01AI067946, R37AI067946)
  • FP7 Ideas: European Research Council (249845)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Health Sciences › Medicine › Oncology › CAR-T cell therapy research
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
Keywords
Wiskott-Aldrich syndrome, lentiviral vectors, hematopoietic stem cell gene therapy, ex vivo gene transfer, metachromatic leukodystrophy, gene therapy safety, immunodeficiency, neurodegenerative diseases, gene expression levels
MeSH terms
Child, Genetic Vectors, Hematopoietic Stem Cells, Humans, Male, Transduction, Genetic, Wiskott-Aldrich Syndrome, Genetic Therapy, Lentivirus, Virus Integration, Hematopoietic Stem Cell Transplantation, Wiskott-Aldrich Syndrome Protein

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