title: Progress toward the genetic treatment of the beta-thalassemias.
abstract: The beta-thalassemias are congenital anemias that are caused by mutations that reduce or abolish expression of the beta-globin gene. They can be cured by allogeneic hematopoietic stem cell (HSC) transplantation, but this therapeutic option is not available to most patients. The transfer of a regulated beta-globin gene in autologous HSCs is a highly attractive alternative treatment. This strategy, which is simple in principle, raises major challenges in terms of controlling expression of the globin transgene, which ideally should be erythroid specific, differentiation- and stage-restricted, elevated, position independent, and sustained over time. Using lentiviral vectors, May et al. demonstrated in 2000 that an optimized combination of proximal and distal transcriptional control elements permits lineage-specific and elevated beta-globin expression, resulting in therapeutic hemoglobin production and correction of anemia in beta-thalassemic mice. Several groups have by now replicated and extended these findings to various mouse models of severe hemoglobinopathies, thus fueling enthusiasm for a potential treatment of beta-thalassemia based on globin gene transfer. Current investigation focuses on safety issues and the need for improved vector production methodologies. The safe implementation of stem cell-based gene therapy requires the prevention of the formation of replication-competent viral genomes and minimization of the risk of insertional oncogenesis. Importantly, globin vectors, in which transcriptional activity is highly restricted, have a lesser risk of activating oncogenes in hematopoietic progenitors than non-tissue-specific vectors, by virtue of their late-stage erythroid specificity. As such, they provide a general paradigm for improving vector safety in stem cell-based gene therapy.
authors.affiliation: Gene Transfer and Gene Expression Laboratory, Memorial Sloan-Kettering Cancer Center, Box 182, 1275 York Ave., New York, NY 10021, USA. m-sadelain@ski.mskcc.org
authors.forename: Michel
authors.initials: M
authors.lastname: Sadelain
authors.forename: Leszek
authors.initials: L
authors.lastname: Lisowski
authors.forename: Selda
authors.initials: S
authors.lastname: Samakoglu
authors.forename: Stefano
authors.initials: S
authors.lastname: Rivella
authors.forename: Chad
authors.initials: C
authors.lastname: May
authors.forename: Isabelle
authors.initials: I
authors.lastname: Riviere
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D015967:Gene Expression Regulation, Viral; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000009:adverse effects; D005822:Genetic Vectors / Q000009:adverse effects / Q000627:therapeutic use; D005914:Globins / Q000096:biosynthesis / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D060588:LIM Domain Proteins; D016086:Lentivirus / Q000235:genetics; D007945:Leukemia, Lymphoid / Q000209:etiology; D019901:Locus Control Region / Q000235:genetics; D008667:Metalloproteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional; D009857:Oncogenes; D011518:Proto-Oncogene Proteins; D012190:Retroviridae / Q000235:genetics; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000628:therapy; D020079:Terminal Repeat Sequences; D019076:Transgenes; D017086:beta-Thalassemia / Q000628:therapy*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; C085117:LMO2 protein, human; C513188:Lmo2 protein, mouse; D008667:Metalloproteins; D011518:Proto-Oncogene Proteins; D005914:Globins