title: Evidence for long-term efficacy and safety of gene therapy for Wiskott-Aldrich syndrome in preclinical models.
abstract: Wiskott-Aldrich Syndrome (WAS) is a life-threatening X-linked disease characterized by immunodeficiency, thrombocytopenia, autoimmunity, and malignancies. Gene therapy could represent a therapeutic option for patients lacking a suitable bone marrow (BM) donor. In this study, we analyzed the long-term outcome of WAS gene therapy mediated by a clinically compatible lentiviral vector (LV) in a large cohort of was(null) mice. We demonstrated stable and full donor engraftment and Wiskott-Aldrich Syndrome protein (WASP) expression in various hematopoietic lineages, up to 12 months after gene therapy. Importantly, we observed a selective advantage for T and B lymphocytes expressing transgenic WASP. T-cell receptor (TCR)-driven T-cell activation, as well as B-cell's ability to migrate in response to CXCL13, was fully restored. Safety was evaluated throughout the long-term follow-up of primary and secondary recipients of WAS gene therapy. WAS gene therapy did not affect the lifespan of treated animals. Both hematopoietic and nonhematopoietic tumors arose, but we excluded the association with gene therapy in all cases. Demonstration of long-term efficacy and safety of WAS gene therapy mediated by a clinically applicable LV is a key step toward the implementation of a gene therapy clinical trial for WAS.
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Marangoni
authors.forename: Marita
authors.initials: M
authors.lastname: Bosticardo
authors.forename: Sabine
authors.initials: S
authors.lastname: Charrier
authors.forename: Elena
authors.initials: E
authors.lastname: Draghici
authors.forename: Michela
authors.initials: M
authors.lastname: Locci
authors.forename: Samantha
authors.initials: S
authors.lastname: Scaramuzza
authors.forename: Cristina
authors.initials: C
authors.lastname: Panaroni
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.forename: Francesca
authors.initials: F
authors.lastname: Sanvito
authors.forename: Claudio
authors.initials: C
authors.lastname: Doglioni
authors.forename: Marie
authors.initials: M
authors.lastname: Liabeuf
authors.forename: Bernard
authors.initials: B
authors.lastname: Gjata
authors.forename: Marie
authors.initials: M
authors.lastname: Montus
authors.forename: Katherine
authors.initials: K
authors.lastname: Siminovitch
authors.forename: Alessandro
authors.initials: A
authors.lastname: Aiuti
authors.forename: Luigi
authors.initials: L
authors.lastname: Naldini
authors.forename: Loïc
authors.initials: L
authors.lastname: Dupré
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Roncarolo
authors.forename: Anne
authors.initials: A
authors.lastname: Galy
authors.forename: Anna
authors.initials: A
authors.lastname: Villa
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D015153:Blotting, Western; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects* / Q000379:methods*; D016130:Immunophenotyping; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016133:Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000378:metabolism; D014923:Wiskott-Aldrich Syndrome / Q000378:metabolism / Q000628:therapy*; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D051316:Wiskott-Aldrich Syndrome Protein