title: Correction of beta-thalassemia major by gene transfer in haematopoietic progenitors of pediatric patients.
abstract: Beta-thalassemia is a common monogenic disorder due to mutations in the beta-globin gene and gene therapy, based on autologous transplantation of genetically corrected haematopoietic stem cells (HSCs), holds the promise to treat patients lacking a compatible bone marrow (BM) donor. We recently showed correction of murine beta-thalassemia by gene transfer in HSCs with the GLOBE lentiviral vector (LV), expressing a transcriptionally regulated human beta-globin gene. Here, we report successful correction of thalassemia major in human cells, by studying a large cohort of pediatric patients of diverse ethnic origin, carriers of different mutations and all candidates to BM transplantation. Extensive characterization of BM-derived CD34(+) cells before and following gene transfer shows the achievement of high frequency of transduction, restoration of haemoglobin A synthesis, rescue from apoptosis and correction of ineffective erythropoiesis. The procedure does not significantly affect the differentiating potential and the relative proportion of haematopoietic progenitors. Analysis of vector integrations shows preferential targeting of transcriptionally active regions, without bias for cancer-related genes. Overall, these results provide a solid rationale for a future clinical translation.
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Emanuela Anna
authors.initials: EA
authors.lastname: Roselli
authors.forename: Riccardo
authors.initials: R
authors.lastname: Mezzadra
authors.forename: Marta Claudia
authors.initials: MC
authors.lastname: Frittoli
authors.forename: Giulietta
authors.initials: G
authors.lastname: Maruggi
authors.forename: Erika
authors.initials: E
authors.lastname: Biral
authors.forename: Fulvio
authors.initials: F
authors.lastname: Mavilio
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Mastropietro
authors.forename: Antonio
authors.initials: A
authors.lastname: Amato
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tonon
authors.forename: Chiara
authors.initials: C
authors.lastname: Refaldi
authors.forename: Maria Domenica
authors.initials: MD
authors.lastname: Cappellini
authors.forename: Marco
authors.initials: M
authors.lastname: Andreani
authors.forename: Guido
authors.initials: G
authors.lastname: Lucarelli
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Roncarolo
authors.forename: Sarah
authors.initials: S
authors.lastname: Marktel
authors.forename: Giuliana
authors.initials: G
authors.lastname: Ferrari
mesh_terms: D000293:Adolescent; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006441:Hemoglobin A / Q000096:biosynthesis; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D008297:Male; D014161:Transduction, Genetic; D014182:Transplantation, Autologous; D017086:beta-Thalassemia / Q000628:therapy*
chemical_list: D006441:Hemoglobin A