Cited by 1,867Virus-based gene therapy researchImmunodeficiency and Autoimmune DisordersCAR-T cell therapy research

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A Serious Adverse Event after Successful Gene Therapy for X-Linked Severe Combined Immunodeficiency

Hacein-Bey-Abina, Salima, von Kalle, Christof, Schmidt, Manfred, Le Deist, Françoise, Wulffraat, Nicolas, McIntyre, Elisabeth, Radford, Isabelle, Villeval, Jean-Luc, Fraser, Christopher C., Cavazzana-Calvo, Marina, Fischer, Alain·2003·New England Journal of Medicine

DOI 10.1056/nejm200301163480314

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Abstract

To the Editor: We recently reported (April 18 issue)1 the sustained correction of X-linked severe combined immunodeficiency disease by ex vivo, retrovirally mediated transfer of the γc gene into CD34+ cells in four of five patients with the disease. These results have since been confirmed in four additional patients with typical X-linked severe combined immunodeficiency. Of the first four successfully treated patients, three continue to do well up to 3.6 years after gene therapy, whereas a serious adverse event occurred in the fourth patient. At a routine checkup 30 months after gene therapy, lymphocytosis consisting of a monoclonal population . . .

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10.1056/NEJMoa012616 · DOI
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Rabbitts TH, 1999, Cancer Res, 59, 1794s
10.3109/08977199309011023 · DOI
10.1056/NEJM199902183400703 · DOI

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The hopes and fears of in utero gene therapy for genetic disease--a review.
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“The recently observed occurrence of oncogenic events after gene therapy with an insertional vector in very young children (Hacein-Bey-Abina et al., 2003) poses the question of a possible increased risk after in utero vector application.”
Background
Personalised genetic intervention for Duchenne muscular dystrophy: antisense oligomers and exon skipping.
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In-Vivo Gene Therapy with Foamy Virus Vectors
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Hematopoietic Stem Cell-Targeted Neonatal Gene Therapy with a Clinically Applicable Lentiviral Vector Corrects Osteopetrosis in oc/oc Mice
Löfvall, H., Rothe, M., Schambach, A., Henriksen, K., Richter, J., & Moscatelli, I. (2019) · Human Gene Therapy · doi:10.1089/hum.2019.047 · Cited by 22
“16, 17 In addition, the incorporation of weaker cellular promoters, such as those being used in the X-linked severe combined immunodeﬁciency (X-SCID) and adenosine deaminase deﬁcient severe combined immunodeﬁciency (ADA-SCID) trials 18–21 (as opposed to strong viral promoters), can increase…”
Multiple Integrated Non-clinical Studies Predict the Safety of Lentivirus-Mediated Gene Therapy for β-Thalassemia
Lidonnici, M. R., Paleari, Y., Tiboni, F., Mandelli, G., Rossi, C., Vezzoli, M., Aprile, A., Lederer, C. W., Ambrosi, A., Chanut, F. J.-A., et al. (2018) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2018.09.001 · Cited by 25
New and improved AAVenues: current status of hemophilia B gene therapy
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Creating a monomeric endonuclease TALE-I-SceI with high specificity and low genotoxicity in human cells
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Gene therapy for retinal diseases
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“[2] Unfortunately, two of the patients in that trial developed T‐cell leukemia because of insertional mutagenesis;[3] and with this, the enthusiasm over gene therapy temporarily waned because of concerns for its potential hazards.”
Background
Transgenic Expression of Human Glial Cell Line-Derived Neurotrophic Factor from Integration-Deficient Lentiviral Vectors is Neuroprotective in a Rodent Model of Parkinson's Disease
Lu‐Nguyen, N., Broadstock, M., Schliesser, M. G., Bartholomae, C. C., Kalle, C. V., Schmidt, M., & Yáñez‐Muñoz, R. J. (2014) · Human Gene Therapy · doi:10.1089/hum.2014.003 · Cited by 24
Self-citation
Hematopoietic Stem Cell Gene Therapy: Assessing the Relevance of Preclinical Models
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“…in a polyclonal background, is similar the clonal dynamics seen in the SCID-X1, X-CGD, and b-thalassemia gene therapy trials (Ott et al., 2006; Hacein-Bey-Abina et al., 2008; Howe et al., 2008; CavazzanaCalvo et al., 2010), and should therefore give a good estimation of the performance of…”
Background
Neutropenia in primary immunodeficiency
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“Infection has been reported to be the major concern associated with viral gene therapy, in rare cases, insertional mutagenesis leading to tumor formation was also observed [23].”
Background
Non-invasive tracking of human haemopoietic CD34+ stem cells in vivo in immunodeficient mice by using magnetic resonance imaging
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Background
Foamy and Lentiviral Vectors Transduce Canine Long-Term Repopulating Cells at Similar Efficiency
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“However, the vector-mediated leukemias observed in the French SCID-X1 study (Hacein-Bey-Abina et al. , 2003) and more recently in the British study have stimulated research to develop safer vector systems.”
Construcción de un vector de expresión derivado de virus adenoasociados para corregir in vitro el defecto genético de la enfermedad de Morquio A
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Retroviral vector production in the National Gene Vector Laboratory at Indiana University
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Genetic manipulation of hematopoietic stem cells.
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Integration pattern of HIV-1 based lentiviral vector carrying recombinant coagulation factor VIII in Sk-Hep and 293T cells
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Method
Clinical hematopoietic stem cell-based gene therapy
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“68,69 This was linked to vector integration near the LMO2 gene, resulting in its up-regulation and likely initiation of the observed blood cancers.”
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Mesenchymal Stem Cells Engineered by Nonviral Vectors: A Powerful Tool in Cancer Gene Therapy
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Background
Secretion of a mammalian chondroitinase ABC aids glial integration at PNS/CNS boundaries
Warren, P. M., Andrews, M. R., Smith, M. E., Bartus, K., Bradbury, E. J., Verhaagen, J., Fawcett, J. W., & Kwok, J. C. F. (2020) · Scientific Reports · doi:10.1038/s41598-020-67526-0 · Cited by 27

Authors: Hacein-Bey-Abina, S., von Kalle, C., Schmidt, M., Le Deist, F., Wulffraat, N., McIntyre, E., Radford, I., Villeval, J.-L., Fraser, C. C., Cavazzana-Calvo, M., & Fischer, A.
ORCID: Schmidt, Manfred
Villeval, Jean-Luc
Fischer, Alain
Venue: New England Journal of Medicine
Publisher: Massachusetts Medical Society
Published: 2003-01-16
Volume: 348
Issue: 3
Pages: 255-256
ISSN: 0028-4793 (ISSN-L)
1533-4406
DOI: 10.1056/nejm200301163480314
OpenAlex: W2323613689
Cited by: 1,867
References: 0
Citations by year: 2026: 29 · 2025: 32 · 2024: 31 · 2023: 25 · 2022: 47 · 2021: 52 · 2020: 46 · 2019: 50 · 2018: 45 · 2017: 63 · 2016: 65 · 2015: 84 · 2014: 87 · 2013: 92 · 2012: 92
FWCI: 86.98
Type: journal article
Language: en
Open access: closed
Locations: New England Journal of Medicine (publishedVersion)
PubMed (publishedVersion)
FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
DigitalGeorgetown (Georgetown University Library) (submittedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
Health Sciences › Medicine › Oncology › CAR-T cell therapy research
Keywords: X-linked severe combined immunodeficiency, gene therapy, adverse events, gene therapy safety
MeSH terms: Chromosomes, Human, Pair 11, DNA-Binding Proteins, Humans, Genetic Linkage, Metalloproteins, Proto-Oncogene Proteins, Retroviridae, Genetic Therapy, Gene Expression, Mutagenesis, Insertional, Severe Combined Immunodeficiency, Lymphocyte Count, Chromosomes, Human, X, Adaptor Proteins, Signal Transducing, Precursor Cell Lymphoblastic Leukemia-Lymphoma, LIM Domain Proteins

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A Serious Adverse Event after Successful Gene Therapy for X-Linked Severe Combined Immunodeficiency

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