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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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Gupta, P. R., & Huckfeldt, R. M. (2017) · Journal of Neural Engineering · doi:10.1088/1741-2552/aa7a27 · Cited by 32
An RNA-targeted therapy for dystrophic epidermolysis bullosa
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“Insertional analysis from treated patients demonstrated several integration sites enriched near transcription start sites (30,31).”
BackgroundGeneration of Integration-free Induced Neural Stem Cells from Mouse Fibroblasts
Kim, S. M., Kim, J.-W., Kwak, T. H., Park, S. W., Kim, K.-P., Park, H., Lim, K. T., Kang, K.-R., Kim, J., Yang, J. H., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.713578 · Cited by 29
“Furthermore, it might also lead to tumor formation, as evidenced by the development of T-cell acute leukemia-like syndrome in the two patients who received integrating retroviruses in a gene therapy trial for the treatment of X-linked severe combined immunodeficiency disease (X-SCID) (42, 43).”
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Changing Paradigm of Hemophilia Management: Extended Half-Life Factor Concentrates and Gene Therapy
Kumar, R., Dunn, A., & Carcao, M. (2016) · Seminars in Thrombosis and Hemostasis · doi:10.1055/s-0035-1568877 · Cited by 27
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“Integration events that activate proto-oncogenes and/or deactivate tumor suppressor genes may result in oncogenesis or silencing of adjacent genes [35].”
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Peptide-based cationic liposome-mediated gene delivery
Zhao, Y., Zhang, S., Cui, S., Wang, B., & Zhang, S. (2011) · Expert Opinion on Drug Delivery · doi:10.1517/17425247.2011.630387 · Cited by 30
“After several accidents [8-10], nonviral vectors gained great attention for they are nonimmunogenic, not oncogenic, easy to produce in large scale and capable to deliver large genetic materials.”
BackgroundInsights into neurogenesis and aging: potential therapy for degenerative disease?
Marr, R. A., Thomas, R. M., & Peterso, D. A. (2010) · Future Neurology · doi:10.2217/fnl.10.33 · Cited by 29
“Furthermore, this approach does not require the genetic alteration of a stem cell population, which carries the risk of n eoplastic transformation [96–98].”
BackgroundFetal gene therapy: Opportunities and risks
Wagner, A. M., Schoeberlein, A., & Surbek, D. (2009) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2009.04.011 · Cited by 29
Optimization of Autologous Muscle Stem Cell Survival in the Denervated Hemilarynx
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Targeting and Intracellular Delivery of Drugs
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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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