title: Lentiviral vector-mediated gene transfer in T cells from Wiskott-Aldrich syndrome patients leads to functional correction.
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 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.
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy, 20132 Milan, Italy.
authors.forename: Loïc
authors.initials: L
authors.lastname: Dupré
authors.forename: Sara
authors.initials: S
authors.lastname: Trifari
authors.forename: Antonia
authors.initials: A
authors.lastname: Follenzi
authors.forename: Francesco
authors.initials: F
authors.lastname: Marangoni
authors.forename: Teresa
authors.initials: T
authors.lastname: Lain de Lera
authors.forename: Antonio
authors.initials: A
authors.lastname: Bernad
authors.forename: Silvana
authors.initials: S
authors.lastname: Martino
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tsuchiya
authors.forename: Claudio
authors.initials: C
authors.lastname: Bordignon
authors.forename: Luigi
authors.initials: L
authors.lastname: Naldini
authors.forename: Alessandro
authors.initials: A
authors.lastname: Aiuti
authors.forename: Maria-Grazia
authors.initials: MG
authors.lastname: Roncarolo
mesh_terms: D000906:Antibodies / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002460:Cell Line; D049109:Cell Proliferation; D015870:Gene Expression; D017930:Genes, Reporter / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000235:genetics; D006801:Humans; D007376:Interleukin-2 / Q000032:analysis / Q000276:immunology; D016086:Lentivirus / Q000235:genetics*; D011506:Proteins / Q000032:analysis / Q000235:genetics*; D011948:Receptors, Antigen, T-Cell / Q000819:agonists; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation* / Q000821:virology; D014161:Transduction, Genetic / Q000379:methods; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics / Q000628:therapy*; D051316:Wiskott-Aldrich Syndrome Protein
chemical_list: D000906:Antibodies; D017252:CD3 Complex; D007376:Interleukin-2; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; C495767:WAS protein, human; D051316:Wiskott-Aldrich Syndrome Protein; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins