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Cited by 532Virus-based gene therapy researchImmunodeficiency and Autoimmune DisordersCAR-T cell therapy research

Stem-Cell Gene Therapy for the Wiskott–Aldrich Syndrome

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Boztug, Kaan, Schmidt, Manfred, Schwarzer, Adrian, Banerjee, Pinaki P., Díez, Inés Avedillo, Dewey, Ricardo A., Böhm, Marie, Nowrouzi, Ali +10 more·2010·New England Journal of Medicine
DOI 10.1056/nejmoa1003548PMC PMC3064520
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Abstract

Sum m a r yThe Wiskott-Aldrich syndrome (WAS) is an X-linked recessive primary immunodeficiency disorder associated with thrombocytopenia, eczema, and autoimmunity.We treated two patients who had this disorder with a transfusion of autologous, genetically modified hematopoietic stem cells (HSC).We found sustained expression of WAS protein expression in HSC, lymphoid and myeloid cells, and platelets after gene therapy.T and B cells, natural killer (NK) cells, and monocytes were functionally corrected.After treatment, the patients' clinical condition markedly improved, with resolution of hemorrhagic diathesis, eczema, autoimmunity, and predisposition to severe infection.Comprehensive insertion-site analysis showed vector integration that targeted multiple genes controlling growth and immunologic responses in a persistently polyclonal hematopoiesis.(Funded by Deutsche Forschungsgemeinschaft and others; German Clinical Trials Register number, DRKS00000330.)T he Wiskott-Aldrich syndrome (WAS) is a complex primary immunodeficiency disorder that is characterized by recurrent infections, thrombocytopenia, eczema, and autoimmunity 1,2 and caused by mutations in WAS. 3 Its gene product, WAS protein (WASP), is a key regulator of actin polymerization in he ma topoietic cells, with domains involved in signaling, cell locomotion, and immunologic-synapse formation.4 The complex biologic features of this disease result from multiple dysfunctions in different subgroups of leukocytes, including defective function of T and B cells, disturbed formation of the NK-cell immunologic synapse, and impaired migratory responses in all leukocyte subgroups.4,5 Severe WAS leads to an early death from infection or bleeding.6 Currently, the only curative therapy consists of allogeneic HSC transplantation, which may be associated with considerable risk of death or complications related to transplantation.7 HSC gene therapy has emerged as an innovative therapeutic strategy for various primary immunodeficiency disorders.8-12 WAS is a promising candidate disease for gene-therapy approaches, since WASP expression is restricted to cells of the hematopoietic system, which grants a proliferative advantage over WASP-negative cells.13,14 Preclinical studies have shown efficient reconstitution of cellular function in vitro and in vivo.13 On the basis of our own preclinical in vitro and in vivo studies, 15,16 we developed a clinical gene-transfer protocol.13 Here we report the results in two young boys who were treated with HSC gene therapy.

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  • HSCT has significant risks of rejection and graft-versus-host disease.

    “the significant risks of rejection and graft-versus-host disease after HSCT make autologous gene-modified HSCT an appealing option [52, 53].”

    From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [53]

    The paper’s introductory passage (indexed under Abstract; page unavailable) says allogeneic HSC transplantation for Wiskott–Aldrich syndrome may carry a considerable risk of death or transplantation-related complications. It does not identify rejection or graft-versus-host disease as those complications, so the cited source supports the general risk but not the two specified risks. (LLM, conf=0.84)

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Cites

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Research works printed but not linked: 23

  1. [1]Puck JM Candotti F Lessons from the Wiskott–Aldrich syndrome N Engl J Med 2006 355 1759 1761 17065636
  2. [2]Notarangelo LD Miao CH Ochs HD Wiskott-Aldrich syndrome Curr Opin Hematol 2008 15 30 36 18043243
  3. [3]Derry JM Ochs HD Francke U Isolation of a novel gene mutated in Wiskott-Aldrich syndrome Cell 1994 78 635 644 8069912
  4. [4]Thrasher AJ Burns SO WASP: a key immunological multitasker Nat Rev Immunol 2010 10 182 192 20182458
  5. [5]Bosticardo M Marangoni F Aiuti A Villa A Grazia Roncarolo M Recent advances in understanding the pathophysiology of Wiskott-Aldrich syndrome Blood 2009 113 6288 6295 19351959
  6. [6]Imai K Morio T Zhu Y Clinical course of patients with WASP gene mutations Blood 2004 103 456 464 12969986
  7. [7]Ozsahin H Cavazzana-Calvo M Notarangelo LD Long-term outcome following hematopoietic stem-cell transplantation in Wiskott-Aldrich syndrome: collaborative study of the European Society for Immunodeficiencies and European Group for Blood and Marrow Transplantation Blood 2008 111 439 445 17901250
  8. [8]Cavazzana-Calvo M Hacein-Bey S de Saint Basile G Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease Science 2000 288 669 672 10784449
  9. [9]Hacein-Bey-Abina S Le Deist F Carlier F Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy N Engl J Med 2002 346 1185 1193 11961146
  10. [10]Aiuti A Slavin S Aker M Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning Science 2002 296 2410 2413 12089448
  11. [11]Aiuti A Cattaneo F Galimberti S Gene therapy for immunodeficiency due to adenosine deaminase deficiency N Engl J Med 2009 360 447 458 19179314
  12. [12]Ott MG Schmidt M Schwarzwaelder K Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1 Nat Med 2006 12 401 409 16582916
  13. [13]Boztug K Dewey RA Klein C Development of hematopoietic stem cell gene therapy for Wiskott-Aldrich syndrome Curr Opin Mol Ther 2006 8 390 395 17078381
  14. [14]Westerberg LS de la Fuente MA Wermeling F WASP confers selective advantage for specific hematopoietic cell populations and serves a unique role in marginal zone B-cell homeostasis and function Blood 2008 112 4139 4147 18772454 PMC2581999
  15. [15]Klein C Nguyen D Lui C-H Gene therapy for Wiskott-Aldrich syndrome: rescue of T-cell signaling and amelioration of colitis upon transplantation of retrovirally transduced hematopoietic stem cells in mice Blood 2003 101 2159 2166 12433691
  16. [16]Dewey RA Avedillo Diez I Ballmaier M Retroviral WASP gene transfer into human hematopoietic stem cells reconstitutes the actin cytoskeleton in myeloid progeny cells differentiated in vitro Exp Hematol 2006 34 1161 1169 16939809
  17. [17]Orange JS Ramesh N Remold-O’Donnell E Wiskott-Aldrich syndrome protein is required for NK cell cytotoxicity and colocalizes with actin to NK cell-activating immunologic synapses Proc Natl Acad Sci U S A 2002 99 11351 11356 12177428 PMC123260
  18. [18]Humblet-Baron S Sather B Anover S Wiskott-Aldrich syndrome protein is required for regulatory T cell homeostasis J Clin Invest 2007 117 407 418 17218989 PMC1764857
  19. [20]Hacein-Bey-Abina S von Kalle C Schmidt M LMO2-associated clonal T-cell proliferations in two patients after gene therapy for SCID-X1 Science 2003 302 415 419 [Erratum, Science 2003;302: 568.] 14564000
  20. [21]Hacein-Bey-Abina S Garrigue A Wang GP Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1 J Clin Invest 2008 118 3132 3142 18688285 PMC2496963
  21. [22]Howe SJ Mansour MR Schwarzwaelder K Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients J Clin Invest 2008 118 3143 3150 18688286 PMC2496964
  22. [23]Stein S Ott MG Schultze-Strasser S Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease Nat Med 2010 16 198 204 20098431
  23. [25]Sabri S Foudi A Boukour S Deficiency in the Wiskott-Aldrich protein induces premature proplatelet formation and platelet production in the bone marrow compartment Blood 2006 108 134 140 16522820

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Authors
Boztug, K., Schmidt, M., Schwarzer, A., Banerjee, P. P., Díez, I. A., Dewey, R. A., Böhm, M., Nowrouzi, A., Ball, C. R., Glimm, H., Naundorf, S., Kühlcke, K., Blasczyk, R., Kondratenko, I., Maródi, L., Orange, J. S., von Kalle, C., & Klein, C.
Affiliations
  • German Cancer Research Center (DE)
  • Medizinische Hochschule Hannover (DE)
  • Children's Hospital of Philadelphia (US)
  • University of Debrecen (HU)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2010-11-11
Volume
363
Issue
20
Pages
1918-1927
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa1003548
PMC
PMC3064520
OpenAlex
W2147859982
Cited by
532
References
2
Citations by year
2026: 10 · 2025: 13 · 2024: 8 · 2023: 22 · 2022: 25 · 2021: 24 · 2020: 26 · 2019: 25 · 2018: 24 · 2017: 37 · 2016: 31 · 2015: 43 · 2014: 63 · 2013: 57 · 2012: 62
FWCI
29.73
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • University of Debrecen Electronic Archive (University of Debrecen) (submittedVersion, other-oa)
Funders
  • Clinical Trial Center, China Medical University Hospital
  • University of Washington
  • Deutsches Krebsforschungszentrum
  • Care-for-Rare Foundation
  • Albert-Ludwigs-Universität Freiburg
  • Medizinischen Hochschule Hannover
  • National Institute of Allergy and Infectious Diseases (R01AI067946, R56AI067946, R37AI067946)
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 cells, autologous stem cell transplantation, primary immunodeficiency, X-linked recessive disorder, vector integration, thrombocytopenia, autoimmunity, atopic dermatitis, polyclonal hematopoiesis
MeSH terms
Humans, Infant, Male, Transplantation, Autologous, Wiskott-Aldrich Syndrome, Genetic Therapy, Mutagenesis, Insertional, Gene Transfer Techniques, Hematopoietic Stem Cell Transplantation, Wiskott-Aldrich Syndrome Protein Family

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