title: Cell and Gene Therapy for the Beta-Thalassemias: Advances and Prospects.
abstract: The beta-thalassemias are inherited anemias caused by mutations that severely reduce or abolish expression of the beta-globin gene. Like sickle cell disease, a related beta-globin gene disorder, they are ideal candidates for performing a genetic correction in patient hematopoietic stem cells (HSCs). The most advanced approach utilizes complex lentiviral vectors encoding the human β-globin gene, as first reported by May et al. in 2000. Considerable progress toward the clinical implementation of this approach has been made in the past five years, based on effective CD34+ cell mobilization and improved lentiviral vector manufacturing. Four trials have been initiated in the United States and Europe. Of 16 evaluable subjects, 6 have achieved transfusion independence. One of them developed a durable clonal expansion, which regressed after several years without transformation. Although globin lentiviral vectors have so far proven to be safe, this occurrence suggests that powerful insulators with robust enhancer-blocking activity will further enhance this approach. The combined discovery of Bcl11a-mediated γ-globin gene silencing and advances in gene editing are the foundations for another gene therapy approach, which aims to reactivate fetal hemoglobin (HbF) production. Its clinical translation will hinge on the safety and efficiency of gene targeting in true HSCs and the induction of sufficient levels of HbF to achieve transfusion independence. Altogether, the progress achieved over the past 15 years bodes well for finding a genetic cure for severe globin disorders in the next decade.
authors.affiliation: 1 Center for Cell Engineering, Memorial Sloan Kettering Cancer Center , New York, New York.
authors.forename: Jorge
authors.initials: J
authors.lastname: Mansilla-Soto
authors.affiliation: 1 Center for Cell Engineering, Memorial Sloan Kettering Cancer Center , New York, New York.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Riviere
authors.affiliation: 1 Center for Cell Engineering, Memorial Sloan Kettering Cancer Center , New York, New York.|2 Department of Pediatrics, Memorial Sloan Kettering Cancer Center , New York, New York.
authors.forename: Farid
authors.initials: F
authors.lastname: Boulad
authors.affiliation: 1 Center for Cell Engineering, Memorial Sloan Kettering Cancer Center , New York, New York.
authors.forename: Michel
authors.initials: M
authors.lastname: Sadelain
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic; D000072669:Gene Editing; D015316:Genetic Therapy / Q000009:adverse effects; D005914:Globins / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D017086:beta-Thalassemia / Q000628:therapy*
chemical_list: D005914:Globins