Efficacy of gene therapy for Wiskott-Aldrich syndrome using a WAS promoter/cDNA-containing lentiviral vector and nonlethal irradiation

Loëc Dupré, Francesco Marangoni, Samantha Scaramuzza, Sara Trifari, Raisa Jofra Hernandez, Alessandro Aiuti, Luigi Naldini, Maria Grazia Roncarolo

Research output: Contribution to journalArticle

Abstract

Wiskott-Aldrich syndrome (WAS) is a life-threatening X-linked primary immunodeficiency characterized by infections, hemorrhages, autoimmune disorders, and lymphomas. Transplantation of genetically corrected autologous hematopoietic stem cells (HSCs) could represent an alternative treatment to allogeneic HSC transplantation, the latter being often associated with severe complications. We used WAS-/- mice to test the efficacy of a gene therapy approach based on nonlethal irradiation followed by transplantation of WAS-/- HSCs transduced with lentiviral vectors encoding the WAS protein (WASP) from either the ubiquitous PGK promoter or the tissue-specific WAS promoter. The procedure resulted in significant levels of engraftment of WASP-expressing T cells, B cells, platelets, and myeloid cells. T cells harbored one or two vector copies and displayed partial to full correction of T cell receptor-driven interleukin-2 production and proliferation. In addition, polymerization of F-actin and localization of WASP at the site of the immunological synapse were restored. The treatment was well tolerated and no pathology was detected by systematic blood analysis and autopsy. The efficacy of WAS gene transfer into HSCs, using the WAS promoter-containing lentiviral vector, combined with nonlethal irradiation provides a strong rationale for the development of gene therapy for WAS patients.

Original languageEnglish
Pages (from-to)303-313
Number of pages11
JournalHuman Gene Therapy
Volume17
Issue number3
DOIs
Publication statusPublished - Mar 2006

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Wiskott-Aldrich Syndrome
Genetic Therapy
Complementary DNA
Hematopoietic Stem Cells
Transplantation
Wiskott-Aldrich Syndrome Protein
Immunological Synapses
T-Lymphocytes
Hematopoietic Stem Cell Transplantation
Myeloid Cells
T-Cell Antigen Receptor
Polymerization
Interleukin-2
Actins
Autopsy
Lymphoma
Proteins
B-Lymphocytes
Blood Platelets
Pathology

ASJC Scopus subject areas

  • Genetics

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Efficacy of gene therapy for Wiskott-Aldrich syndrome using a WAS promoter/cDNA-containing lentiviral vector and nonlethal irradiation. / Dupré, Loëc; Marangoni, Francesco; Scaramuzza, Samantha; Trifari, Sara; Hernandez, Raisa Jofra; Aiuti, Alessandro; Naldini, Luigi; Roncarolo, Maria Grazia.

In: Human Gene Therapy, Vol. 17, No. 3, 03.2006, p. 303-313.

Research output: Contribution to journalArticle

Dupré, Loëc ; Marangoni, Francesco ; Scaramuzza, Samantha ; Trifari, Sara ; Hernandez, Raisa Jofra ; Aiuti, Alessandro ; Naldini, Luigi ; Roncarolo, Maria Grazia. / Efficacy of gene therapy for Wiskott-Aldrich syndrome using a WAS promoter/cDNA-containing lentiviral vector and nonlethal irradiation. In: Human Gene Therapy. 2006 ; Vol. 17, No. 3. pp. 303-313.
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