title: Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome.
abstract: Wiskott-Aldrich syndrome (WAS) is an inherited immunodeficiency caused by mutations in the gene encoding WASP, a protein regulating the cytoskeleton. Hematopoietic stem/progenitor cell (HSPC) transplants can be curative, but, when matched donors are unavailable, infusion of autologous HSPCs modified ex vivo by gene therapy is an alternative approach. We used a lentiviral vector encoding functional WASP to genetically correct HSPCs from three WAS patients and reinfused the cells after a reduced-intensity conditioning regimen. All three patients showed stable engraftment of WASP-expressing cells and improvements in platelet counts, immune functions, and clinical scores. Vector integration analyses revealed highly polyclonal and multilineage haematopoiesis resulting from the gene-corrected HSPCs. Lentiviral gene therapy did not induce selection of integrations near oncogenes, and no aberrant clonal expansion was observed after 20 to 32 months. Although extended clinical observation is required to establish long-term safety, lentiviral gene therapy represents a promising treatment for WAS.
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy, Division of Regenerative Medicine, Stem Cells, and Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy. aiuti.alessandro@hsr.it
authors.forename: Alessandro
authors.initials: A
authors.lastname: Aiuti
authors.forename: Luca
authors.initials: L
authors.lastname: Biasco
authors.forename: Samantha
authors.initials: S
authors.lastname: Scaramuzza
authors.forename: Francesca
authors.initials: F
authors.lastname: Ferrua
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Cicalese
authors.forename: Cristina
authors.initials: C
authors.lastname: Baricordi
authors.forename: Francesca
authors.initials: F
authors.lastname: Dionisio
authors.forename: Andrea
authors.initials: A
authors.lastname: Calabria
authors.forename: Stefania
authors.initials: S
authors.lastname: Giannelli
authors.forename: Maria Carmina
authors.initials: MC
authors.lastname: Castiello
authors.forename: Marita
authors.initials: M
authors.lastname: Bosticardo
authors.forename: Costanza
authors.initials: C
authors.lastname: Evangelio
authors.forename: Andrea
authors.initials: A
authors.lastname: Assanelli
authors.forename: Miriam
authors.initials: M
authors.lastname: Casiraghi
authors.forename: Sara
authors.initials: S
authors.lastname: Di Nunzio
authors.forename: Luciano
authors.initials: L
authors.lastname: Callegaro
authors.forename: Claudia
authors.initials: C
authors.lastname: Benati
authors.forename: Paolo
authors.initials: P
authors.lastname: Rizzardi
authors.forename: Danilo
authors.initials: D
authors.lastname: Pellin
authors.forename: Clelia
authors.initials: C
authors.lastname: Di Serio
authors.forename: Manfred
authors.initials: M
authors.lastname: Schmidt
authors.forename: Christof
authors.initials: C
authors.lastname: Von Kalle
authors.forename: Jason
authors.initials: J
authors.lastname: Gardner
authors.forename: Nalini
authors.initials: N
authors.lastname: Mehta
authors.forename: Victor
authors.initials: V
authors.lastname: Neduva
authors.forename: David J
authors.initials: DJ
authors.lastname: Dow
authors.forename: Anne
authors.initials: A
authors.lastname: Galy
authors.forename: Roberto
authors.initials: R
authors.lastname: Miniero
authors.forename: Andrea
authors.initials: A
authors.lastname: Finocchi
authors.forename: Ayse
authors.initials: A
authors.lastname: Metin
authors.forename: Pinaki P
authors.initials: PP
authors.lastname: Banerjee
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Orange
authors.forename: Stefania
authors.initials: S
authors.lastname: Galimberti
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Valsecchi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Biffi
authors.forename: Eugenio
authors.initials: E
authors.lastname: Montini
authors.forename: Anna
authors.initials: A
authors.lastname: Villa
authors.forename: Fabio
authors.initials: F
authors.lastname: Ciceri
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Roncarolo
authors.forename: Luigi
authors.initials: L
authors.lastname: Naldini
mesh_terms: D002648:Child; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D016086:Lentivirus; D008297:Male; D014161:Transduction, Genetic; D016662:Virus Integration; D014923:Wiskott-Aldrich Syndrome / Q000628:therapy*; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics*
chemical_list: D051316:Wiskott-Aldrich Syndrome Protein