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A Serious Adverse Event after Successful Gene Therapy for X-Linked Severe Combined Immunodeficiency
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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“Lentiviral vectors are considered safer than gamma-retroviral vectors in terms of their semi-random integration patterns, as gene integration does not preferentially occur in start regions of active genes (93-95).”
From Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy (2021) · cites this paper as [93]
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“In an otherwise quite successful gene therapy trial treating human X-SCID, the gene therapy vector used integrated near a proto-oncogene and caused leukemia in three of the patients treated [5,6].”
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“In the context of cell-based medicine, lack of control over the transgene integration site can result in adverse events due to insertional mutagenesis (1).”
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Current Status of Pharmaceutical and Genetic Therapeutic Approaches to Treat DMD
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Biological Approaches to Bone Regeneration by Gene Therapy
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“First, the integrated retrovirus can disrupt normal cell function by insertional mutagenesis, an event that, unfortunately, was recently observed in some patients (Hacein-Bey-Abina et al., 2003; Noguchi, 2003).”
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Advances in stem cell research and therapeutic development
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Sonoporation: mechanistic insights and ongoing challenges for gene transfer.
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In vivo reversion to normal of inherited mutations in humans
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“38 A risk of malignancy following random integration of retroviral vectors at an oncogenic site had been hypothesised from the earliest in vitro studies.”
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Hematopoietic Stem Cell Gene Therapy: Progress and Lessons Learned
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Genetic treatment of a molecular disorder: gene therapy approaches to sickle cell disease
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“These many insertions carry an inherent risk for insertional oncogenesis or loss of appropriate gene regulation by mechanisms such as aberrant splicing.(128,136) Although safetymay bemodulated by vector design, including the use of insulators, optimal cellular promoters, and lentiviral vectors,(140,141) it may not be…”
Background
Metadata
- 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.
- 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
- 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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