Lentiviral vector-mediated gene transfer in T cells from Wiskott-Aldrich syndrome patients leads to functional correction

Loïc Dupré, Sara Trifari, Antonia Follenzi, Francesco Marangoni, Teresa Lain de Lera, Antonio Bernad, Silvana Martino, Shigeru Tsuchiya, Claudio Bordignon, Luigi Naldini, Alessandro Aiuti, Maria Grazia Roncarolo

Research output: Contribution to journalArticle

Abstract

Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency with a median survival below the age of 20 due to infections, severe hemorrhage, and lymphomas. Transplantation of hematopoietic stem cells from HLA-identical sibling donors is a resolutive treatment, but is available for a minority of patients. Transplantation of genetically corrected autologous hematopoietic stem cells or T cells could represent an alternative treatment applicable to all patients. We investigated whether WAS gene transfer with MMLV-based oncoretroviral and HIV-based lentiviral vectors could restore normal functions of patients' T cells. T cells transduced either with lentiviral vectors expressing the WAS protein (WASP) from the ubiquitous PGK promoter or the tissue-specific WASP promoter or with an oncoretroviral vector expressing WASP from the LTR, reached normal levels of WASP with correction of functional defects, including proliferation, IL-2 production, and lipid raft upregulation. Lentiviral vectors transduced T cells from WAS patients at higher rates, compared to oncoretroviral vectors, and efficiently transduced both activated and naïve WAS T cells. Furthermore, a selective growth advantage of T cells corrected with the lentiviral vectors was demonstrated. The observation that lentiviral vector-mediated gene transfer results in correction of T cell defects in vitro supports their application for gene therapy in WAS patients.

Original languageEnglish
Pages (from-to)903-915
Number of pages13
JournalMolecular Therapy
Volume10
Issue number5
DOIs
Publication statusPublished - Nov 2004

Fingerprint

Wiskott-Aldrich Syndrome
T-Lymphocytes
Genes
Wiskott-Aldrich Syndrome Protein
Proteins
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells
Genetic Therapy
Interleukin-2
Siblings
Lymphoma
Up-Regulation
Transplantation
Tissue Donors
HIV
Hemorrhage
Lipids
Survival
Therapeutics
Growth

Keywords

  • Functional correction
  • Lentiviral vectors
  • Oncoretroviral vectors
  • Primary immunodeficiency
  • T lymphocytes

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Dupré, L., Trifari, S., Follenzi, A., Marangoni, F., Lain de Lera, T., Bernad, A., ... Roncarolo, M. G. (2004). Lentiviral vector-mediated gene transfer in T cells from Wiskott-Aldrich syndrome patients leads to functional correction. Molecular Therapy, 10(5), 903-915. https://doi.org/10.1016/j.ymthe.2004.08.008

Lentiviral vector-mediated gene transfer in T cells from Wiskott-Aldrich syndrome patients leads to functional correction. / Dupré, Loïc; Trifari, Sara; Follenzi, Antonia; Marangoni, Francesco; Lain de Lera, Teresa; Bernad, Antonio; Martino, Silvana; Tsuchiya, Shigeru; Bordignon, Claudio; Naldini, Luigi; Aiuti, Alessandro; Roncarolo, Maria Grazia.

In: Molecular Therapy, Vol. 10, No. 5, 11.2004, p. 903-915.

Research output: Contribution to journalArticle

Dupré, L, Trifari, S, Follenzi, A, Marangoni, F, Lain de Lera, T, Bernad, A, Martino, S, Tsuchiya, S, Bordignon, C, Naldini, L, Aiuti, A & Roncarolo, MG 2004, 'Lentiviral vector-mediated gene transfer in T cells from Wiskott-Aldrich syndrome patients leads to functional correction', Molecular Therapy, vol. 10, no. 5, pp. 903-915. https://doi.org/10.1016/j.ymthe.2004.08.008
Dupré, Loïc ; Trifari, Sara ; Follenzi, Antonia ; Marangoni, Francesco ; Lain de Lera, Teresa ; Bernad, Antonio ; Martino, Silvana ; Tsuchiya, Shigeru ; Bordignon, Claudio ; Naldini, Luigi ; Aiuti, Alessandro ; Roncarolo, Maria Grazia. / Lentiviral vector-mediated gene transfer in T cells from Wiskott-Aldrich syndrome patients leads to functional correction. In: Molecular Therapy. 2004 ; Vol. 10, No. 5. pp. 903-915.
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