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Klein Lab - Research

Gene therapy for hematopoietic stem cells

Monogenic disorders of the blood and immune system may predispose patients to recurrent infections, autoimmunity, allergy, and cancer. In general, allogenic hematopoietic stem cell transplantation (HSCT) is considered as the standard curative therapy option for primary immunodeficiency disorders (PIDs). However, it is limited by donor availability and is also associated with significant morbidity and mortality. HSC gene therapy with gene addition by retroviral or lentiviral vectors has then emerged as an alternative therapeutic strategy for PIDs, including Wiskott-Aldrich syndrome (WAS).

WAS is a complex life-threatening PID characterized by recurrent pyogenic, viral and fungal infections, thrombocytopenia and autoimmunity. It is an X-linked disorder caused by loss of function mutations in the gene encoding the Wiskott-Aldrich syndrome protein (WASP). WASP-deficiency leads to multiple dysfunctions in different subgroups of leukocytes, including defective T and B cell function, disturbed formation of the NK cell immunological synapse and impaired migratory responses in all leukocyte subgroups.

We started a hematopoietic stem cell gene therapy trial using γ-retroviral vector to reconstitute WASP expression. Between 2006 and 2009, 10 patients with severe WAS were enrolled for the trial. After gene therapy, 9 of 10 patients showed sustained engraftment and correction of WASP expression in lymphoid and myeloid cells and platelets. Gene therapy resulted in partial or complete resolution of immunodeficiency, autoimmunity, and bleeding diathesis. However, 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 proto-oncogenes LMO2 (six T-ALL), MDS1 (two AML), or MN1 (one AML)).

Our study showed hematopoietic stem cell gene therapy for WAS is feasible and effective, but the use of γ-vectors is associated with a substantial risk of leukemogenesis. We now hypothesize that WAS is associated with decreased genomic stability and continue to work on the development of efficacious and safe techniques for the genetic engineering of HSC, to cure WAS and other primary immunodeficiency diseases.


Boztug K, Dewey RA, Klein C (2006) Development of hematopoietic stem cell gene therapy for Wiskott-Aldrich syndrome. Curr Opin Mol Ther 8: 390-395. PubMed

Boztug K, Schmidt M, Schwarzer A, Banerjee PP, Diez IA, Dewey RA, Bohm M, Nowrouzi A, Ball CR, Glimm H, Naundorf S, Kuhlcke K, Blasczyk R, Kondratenko I, Marodi L, Orange JS, von Kalle C, Klein C (2010) Stem-cell gene therapy for the Wiskott-Aldrich syndrome. The New England journal of medicine 363: 1918-1927. PubMed

Braun CJ, Boztug K, Paruzynski A, Witzel M, Schwarzer A, Rothe M, Modlich U, Beier R, Gohring G, Steinemann D, Fronza R, Ball CR, Haemmerle R, Naundorf S, Kuhlcke K, Rose M, Fraser C, Mathias L, Ferrari R, Abboud MR, Al-Herz W, Kondratenko I, Marodi L, Glimm H, Schlegelberger B, Schambach A, Albert MH, Schmidt M, von Kalle C, Klein C (2014) Gene therapy for Wiskott-Aldrich syndrome--long-term efficacy and genotoxicity. Science translational medicine 6: 227ra233. PubMed