Gene therapy for Wiskott-Aldrich syndrome–long-term efficacy and genotoxicity
Open accessAbstract
Wiskott-Aldrich syndrome (WAS) is characterized by microthrombocytopenia, immunodeficiency, autoimmunity, and susceptibility to malignancies. In our hematopoietic stem cell gene therapy (GT) trial using a γ-retroviral vector, 9 of 10 patients showed sustained engraftment and correction of WAS protein (WASP) expression in lymphoid and myeloid cells and platelets. GT resulted in partial or complete resolution of immunodeficiency, autoimmunity, and bleeding diathesis. Analysis of retroviral insertion sites revealed >140,000 unambiguous integration sites and a polyclonal pattern of hematopoiesis in all patients early after GT. Seven patients developed acute leukemia [one acute myeloid leukemia (AML), four T cell acute lymphoblastic leukemia (T-ALL), and two primary T-ALL with secondary AML associated with a dominant clone with vector integration at the LMO2 (six T-ALL), MDS1 (two AML), or MN1 (one AML) locus]. Cytogenetic analysis revealed additional genetic alterations such as chromosomal translocations. This study shows that hematopoietic stem cell GT for WAS is feasible and effective, but the use of γ-retroviral vectors is associated with a substantial risk of leukemogenesis.
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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.
“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 [95]
Cites
A Mathematical Theory of Communication
Shannon, C. E. (1948) · Bell System Technical Journal · doi:10.1002/j.1538-7305.1948.tb01338.x · Cited by 88,486 · see citing works
A census of human cancer genes
Futreal, P. A., Coin, L., Marshall, M., Down, T., Hubbard, T., Wooster, R., Rahman, N., & Stratton, M. R. (2004) · Nature Reviews Cancer · doi:10.1038/nrc1299 · Cited by 3,184 · see citing works
A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency
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., et al. (2003) · New England Journal of Medicine · doi:10.1056/nejm200301163480314 · Cited by 1,867 · cited 8× · see citing works
“(C to G) The localization of the CIS is shown forMDS1 (C), EVI1 (D), PRDM16 (E), LMO2 (F), and CCND2 (G).”
BackgroundInfluentialSelf-citationHigh-resolution insertion-site analysis by linear amplification-mediated PCR (LAM-PCR)
Schmidt, M., Schwarzwaelder, K., Bartholomae, C., Zaoui, K., Ball, C., Pilz, I., Braun, S., Glimm, H., & von Kalle, C. (2007) · Nature Methods · doi:10.1038/nmeth1103 · Cited by 328 · see citing works
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Dunbar, C. E., High, K. A., Joung, J. K., Kohn, D. B., Ozawa, K., & Sadelain, M. (2018) · Science · doi:10.1126/science.aan4672 · Cited by 1,410 · see citing works
Gene therapy returns to centre stage
Naldini, L. (2015) · Nature · doi:10.1038/nature15818 · Cited by 1,184 · see citing works
Gene therapy clinical trials worldwide to 2017: An update
Ginn, S. L., Amaya, A. K., Alexander, I. E., Edelstein, M., & Abedi, M. R. (2018) · The Journal of Gene Medicine · doi:10.1002/jgm.3015 · Cited by 903 · see citing works
Delivery technologies for genome editing
Yin, H., Kauffman, K. J., & Anderson, D. G. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.280 · Cited by 597 · see citing works
Targeted genome editing in human repopulating haematopoietic stem cells
Genovese, P., Schiroli, G., Escobar, G., Di Tomaso, T., Firrito, C., Calabria, A., Moi, D., Mazzieri, R., Bonini, C., Holmes, M. C., et al. (2014) · Nature · doi:10.1038/nature13420 · Cited by 555 · see citing works
High, K. A., & Roncarolo, M. G. (2019) · New England Journal of Medicine · doi:10.1056/nejmra1706910 · Cited by 555 · see citing works
Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy
Abou-el-Enein, M., Elsallab, M., Feldman, S. A., Fesnak, A. D., Heslop, H. E., Marks, P., Till, B. G., Bauer, G., & Savoldo, B. (2021) · Blood Cancer Discovery · doi:10.1158/2643-3230.bcd-21-0084 · Cited by 321 · see citing works
Wang, J., Exline, C. M., DeClercq, J. J., Llewellyn, G. N., Hayward, S. B., Li, P. W.-L., Shivak, D. A., Surosky, R. T., Gregory, P. D., Holmes, M. C., et al. (2015) · Nature Biotechnology · doi:10.1038/nbt.3408 · Cited by 261 · see citing works
Negre, O., Eggimann, A.-V., Beuzard, Y., Ribeil, J.-A., Bourget, P., Borwornpinyo, S., Hongeng, S., Hacein-Bey, S., Cavazzana, M., Leboulch, P., et al. (2016) · Human Gene Therapy · doi:10.1089/hum.2016.007 · Cited by 159 · see citing works
Liver-directed lentiviral gene therapy in a dog model of hemophilia B
Cantore, A., Ranzani, M., Bartholomae, C. C., Volpin, M., Valle, P. D., Sanvito, F., Sergi, L. S., Gallina, P., Benedicenti, F., Bellinger, D., et al. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aaa1405 · Cited by 158 · see citing works
Self-citationWang, J., DeClercq, J. J., Hayward, S. B., Li, P. W.-L., Shivak, D. A., Gregory, P. D., Lee, G., & Holmes, M. C. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkv1121 · Cited by 128 · see citing works
Cell and Gene Therapy for the Beta-Thalassemias: Advances and Prospects
Mansilla-Soto, J., Riviere, I., Boulad, F., & Sadelain, M. (2016) · Human Gene Therapy · doi:10.1089/hum.2016.037 · Cited by 83 · see citing works
Tipanee, J., Samara-Kuko, E., Gevaert, T., Chuah, M. K., & VandenDriessche, T. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.06.006 · Cited by 76 · see citing works
Brendel, C., Negre, O., Rothe, M., Guda, S., Parsons, G., Harris, C., McGuinness, M., Abriss, D., Tsytsykova, A., Klatt, D., et al. (2020) · Molecular Therapy - Methods & Clinical Development · doi:10.1016/j.omtm.2020.03.015 · Cited by 72 · see citing works
Self-citationLi, S., Datta, S., Brabbit, E., Love, Z., Woytowicz, V., Flattery, K., Capri, J., Yao, K., Wu, S., Imboden, M., et al. (2021) · Gene Therapy · doi:10.1038/s41434-020-0134-z · Cited by 68 · see citing works
The old and the new: Prospects for non-integrating lentiviral vector technology
Apolonia, L. (2020) · Viruses · doi:10.3390/v12101103 · Cited by 58 · see citing works
Curative options for sickle cell disease: haploidentical stem cell transplantation or gene therapy?
Leonard, A., Tisdale, J., & Abraham, A. (2020) · British Journal of Haematology · doi:10.1111/bjh.16437 · Cited by 45 · see citing works
Singh, S., Khan, I., Khim, S., Seymour, B., Sommer, K., Wielgosz, M., Norgaard, Z., Kiem, H.-P., Adair, J., Liggitt, D., et al. (2017) · Molecular Therapy - Methods & Clinical Development · doi:10.1016/j.omtm.2016.11.001 · Cited by 13 · see citing works
- Authors
- Braun, C. J., Boztug, K., Paruzynski, A., Witzel, M., Schwarzer, A., Rothe, M., Modlich, U., Beier, R., Göhring, G., Steinemann, D., Fronza, R., Ball, C. R., Haemmerle, R., Naundorf, S., Kühlcke, K., Rose, M., Fraser, C., Mathias, L., Ferrari, R., Abboud, M. R., Al-Herz, W., Kondratenko, I., Maródi, L., Glimm, H., Schlegelberger, B., Schambach, A., Albert, M. H., Schmidt, M., von Kalle, C., & Klein, C.
- Affiliations
- Dr. von Hauner Children’s Hospital, Ludwig Maximilians University Munich, 80337 Munich, Germany.
- Department of Pediatric Hematology/Oncology, Hannover Medical School, 30625 Hannover, Germany.
- German Cancer Research Center (DE)
- Ludwig-Maximilians-Universität München (DE)
- Medizinische Hochschule Hannover (DE)
- EUFETS AG, 55743 Idar-Oberstein, Germany.
- Johannes Wesling Klinikum Minden (DE)
- Children's Health Queensland Hospital and Health Service (AU)
- Loma Linda University Medical Center (US)
- Children’s Hospital Kemperhof, 56073 Koblenz, Germany.
- American University of Beirut Medical Center (LB)
- Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait.
- Department of Clinical Immunology, Russian Clinical Children’s Hospital, 117513 Moscow, Russia.
- University of Debrecen (HU)
- Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, 69120 Heidelberg, Germany.
- Corresponding author
- Paruzynski, Anna
- Witzel, Maximilian
- Schmidt, Manfred
- Klein, Christoph
- ORCID
- Venue
- Science Translational Medicine
- Published
- 2014-03-12
- Volume
- 6
- Issue
- 227
- Pages
- 227ra33-227ra33
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- OpenAlex
- W2130174662
- Cited by
- 562
- References
- 4
- Citations by year
- 2026: 22 · 2025: 23 · 2024: 38 · 2023: 39 · 2022: 49 · 2021: 48 · 2020: 53 · 2019: 46 · 2018: 45 · 2017: 69 · 2016: 50 · 2015: 42 · 2014: 36 · 2013: 1
- FWCI
- 43.13
- Type
- journal article
- Language
- en
- Update notices
- correction (2014-09-17)
- Open access
- green
- hdl.handle.net
- Licence
- other-oa
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- University of Debrecen Electronic Archive (University of Debrecen) (submittedVersion, other-oa)
- 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
- Wiskott-Aldrich syndrome, hematopoietic stem cell gene therapy, gammaretroviral vectors, WASP protein, genotoxicity, leukemogenesis, T-cell acute lymphoblastic leukemia, acute myeloid leukemia, LMO2, MN1, chromosomal translocation, immunodeficiency, autoimmunity, platelet count
- MeSH terms
- Adolescent, Animals, Blood Platelets, Child, Child, Preschool, Clone Cells, Colitis, Hematopoietic Stem Cells, Humans, Leukocytes, Mononuclear, Lymphocytes, Mutagens, Thrombocytopenia, Transplantation, Autologous, Wiskott-Aldrich Syndrome, Genetic Therapy, Mice, Inbred NOD, Treatment Outcome, Hematopoietic Stem Cell Transplantation, Disease Progression, Wiskott-Aldrich Syndrome Protein, Mice, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
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