Gene therapy for Wiskott-Aldrich syndrome-long-term efficacy and genotoxicity

Christian Jörg Braun, Kaan Boztug, Anna Paruzynski, Maximilian Witzel, Adrian Schwarzer, Michael Rothe, Ute Modlich, Rita Beier, Gudrun Göhring, Doris Steinemann, Raffaele Fronza, Claudia Regina Ball, Reinhard Haemmerle, Sonja Naundorf, Klaus Kühlcke, Martina Rose, Chris Fraser, Liesl Mathias, Rudolf Ferrari, Miguel R. Abboud & 10 others Waleed Al-Herz, Irina Kondratenko, L. Máródi, Hanno Glimm, Brigitte Schlegelberger, Axel Schambach, Michael Heinrich Albert, Manfred Schmidt, Christof Van Kalle, Christoph Klein

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Abstract

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.

Original languageEnglish
Article number227ra33
JournalScience Translational Medicine
Volume6
Issue number227
DOIs
Publication statusPublished - Mar 12 2014

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Wiskott-Aldrich Syndrome
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Acute Myeloid Leukemia
Genetic Therapy
Cell- and Tissue-Based Therapy
Hematopoietic Stem Cells
Autoimmunity
Wiskott-Aldrich Syndrome Protein
Genetic Translocation
Cytogenetic Analysis
Disease Susceptibility
Hematopoiesis
Myeloid Cells
Leukemia
Blood Platelets
Clone Cells
Lymphocytes
Hemorrhage
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Braun, C. J., Boztug, K., Paruzynski, A., Witzel, M., Schwarzer, A., Rothe, M., ... Klein, C. (2014). Gene therapy for Wiskott-Aldrich syndrome-long-term efficacy and genotoxicity. Science Translational Medicine, 6(227), [227ra33]. https://doi.org/10.1126/scitranslmed.3007280

Gene therapy for Wiskott-Aldrich syndrome-long-term efficacy and genotoxicity. / Braun, Christian Jörg; Boztug, Kaan; Paruzynski, Anna; Witzel, Maximilian; Schwarzer, Adrian; Rothe, Michael; Modlich, Ute; Beier, Rita; Göhring, Gudrun; Steinemann, Doris; Fronza, Raffaele; Ball, Claudia Regina; Haemmerle, Reinhard; Naundorf, Sonja; Kühlcke, Klaus; Rose, Martina; Fraser, Chris; Mathias, Liesl; Ferrari, Rudolf; Abboud, Miguel R.; Al-Herz, Waleed; Kondratenko, Irina; Máródi, L.; Glimm, Hanno; Schlegelberger, Brigitte; Schambach, Axel; Albert, Michael Heinrich; Schmidt, Manfred; Van Kalle, Christof; Klein, Christoph.

In: Science Translational Medicine, Vol. 6, No. 227, 227ra33, 12.03.2014.

Research output: Contribution to journalArticle

Braun, CJ, Boztug, K, Paruzynski, A, Witzel, M, Schwarzer, A, Rothe, M, Modlich, U, Beier, R, Göhring, G, Steinemann, D, Fronza, R, Ball, CR, Haemmerle, R, Naundorf, S, Kühlcke, K, Rose, M, Fraser, C, Mathias, L, Ferrari, R, Abboud, MR, Al-Herz, W, Kondratenko, I, Máródi, L, Glimm, H, Schlegelberger, B, Schambach, A, Albert, MH, Schmidt, M, Van Kalle, C & Klein, C 2014, 'Gene therapy for Wiskott-Aldrich syndrome-long-term efficacy and genotoxicity', Science Translational Medicine, vol. 6, no. 227, 227ra33. https://doi.org/10.1126/scitranslmed.3007280
Braun CJ, Boztug K, Paruzynski A, Witzel M, Schwarzer A, Rothe M et al. Gene therapy for Wiskott-Aldrich syndrome-long-term efficacy and genotoxicity. Science Translational Medicine. 2014 Mar 12;6(227). 227ra33. https://doi.org/10.1126/scitranslmed.3007280
Braun, Christian Jörg ; Boztug, Kaan ; Paruzynski, Anna ; Witzel, Maximilian ; Schwarzer, Adrian ; Rothe, Michael ; Modlich, Ute ; Beier, Rita ; Göhring, Gudrun ; Steinemann, Doris ; Fronza, Raffaele ; Ball, Claudia Regina ; Haemmerle, Reinhard ; Naundorf, Sonja ; Kühlcke, Klaus ; Rose, Martina ; Fraser, Chris ; Mathias, Liesl ; Ferrari, Rudolf ; Abboud, Miguel R. ; Al-Herz, Waleed ; Kondratenko, Irina ; Máródi, L. ; Glimm, Hanno ; Schlegelberger, Brigitte ; Schambach, Axel ; Albert, Michael Heinrich ; Schmidt, Manfred ; Van Kalle, Christof ; Klein, Christoph. / Gene therapy for Wiskott-Aldrich syndrome-long-term efficacy and genotoxicity. In: Science Translational Medicine. 2014 ; Vol. 6, No. 227.
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AU - Schwarzer, Adrian

AU - Rothe, Michael

AU - Modlich, Ute

AU - Beier, Rita

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AU - Ferrari, Rudolf

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AU - Al-Herz, Waleed

AU - Kondratenko, Irina

AU - Máródi, L.

AU - Glimm, Hanno

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N2 - 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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