title: Globin gene transfer for treatment of the beta-thalassemias and sickle cell disease.
abstract: The beta-thalassemias and sickle cell disease are severe congenital anemias that are caused by mutations that alter the production of the beta chain of hemoglobin. Allogeneic hematopoietic stem cell (HSC) transplantation is curative, but this therapeutic option is not available to the majority of patients. The transfer of a functional globin gene in autologous HCSs thus represents a highly attractive alternative treatment. This strategy, simple in principle, raises major challenges in terms of controlling the expression of the globin transgene, which ideally should be erythroid specific, differentiation-stage restricted, elevated, position independent, and sustained over time. Using lentiviral vectors, we have demonstrated that an optimised combination of proximal and distal transcriptional control elements permits lineage-specific, elevated expression of the beta-globin gene, resulting in therapeutic hemoglobin production and correction of anemia in beta-thalassemic mice. Several groups have now confirmed and extended these findings in various mouse models of severe hemoglobinopathies, thus generating enthusiasm for a genetic treatment based on globin gene transfer. Furthermore, globin vectors represent a general paradigm for the regulation of transgene function and the improvement of vector safety by restricting transgene expression to the differentiated progeny within a single lineage, thereby reducing the risk of activating oncogenes in hematopoietic progenitors. Here we review the principles underlying the genesis of regulated vectors for stem cell therapy.
authors.affiliation: Laboratory of Gene Transfer and Gene Expression, Gene Transfer and Somatic Cell Engineering Facility, Box 182 Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. m-sadelain@ski.mskcc.org
authors.forename: Michel
authors.initials: M
authors.lastname: Sadelain
authors.forename: Stefano
authors.initials: S
authors.lastname: Rivella
authors.forename: Leszek
authors.initials: L
authors.lastname: Lisowski
authors.forename: Selda
authors.initials: S
authors.lastname: Samakoglu
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rivière
mesh_terms: D000755:Anemia, Sickle Cell / Q000628:therapy; D000818:Animals; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005914:Globins / Q000235:genetics / Q000627:therapeutic use*; D006453:Hemoglobinopathies / Q000628:therapy*; D006801:Humans; D051379:Mice; D017086:beta-Thalassemia / Q000628:therapy
chemical_list: D005914:Globins