Lentiviral Vector-Mediated Gene Transfer in T Cells from Wiskott-Aldrich Syndrome Patients Leads to Functional Correction

• Published in: Molecular therapy Vol. 10; no. 5; pp. 903 - 915
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Limited 01.11.2004
• Subjects: Antibodies - immunology; CD3 Complex - immunology; Cell Line; Cell Proliferation; Cloning; Gene Expression; Gene therapy; Genes, Reporter - genetics; Genetic Therapy - methods; Genetic Vectors - genetics; Green Fluorescent Proteins - analysis; Green Fluorescent Proteins - genetics; Humans; Immune system; Infections; Interleukin-2 - analysis; Interleukin-2 - immunology; Lentivirus - genetics; Lymphocytes; Lymphoma; Oncology; Proteins; Proteins - analysis; Proteins - genetics; Receptors, Antigen, T-Cell - agonists; Stem cells; T cell receptors; T-Lymphocytes - immunology; T-Lymphocytes - transplantation; T-Lymphocytes - virology; Transduction, Genetic - methods; Vectors (Biology); Wiskott-Aldrich Syndrome - genetics; Wiskott-Aldrich Syndrome - therapy; Wiskott-Aldrich Syndrome Protein; Italy
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2004.08.008

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 naive 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.