In vivo selection of genetically modified erythroblastic progenitors leads to long-term correction of β-thalassemia

Annarita Miccio, Rossano Cesari, Francesco Lotti, Claudia Rossi, Francesca Sanvito, Maurilio Ponzoni, Samantha J E Routledge, Cheok Man Chow, Michael N. Antoniou, Giuliana Ferrari

Research output: Contribution to journalArticlepeer-review


Gene therapy for β-thalassemia requires stable transfer of a β-globin gene into hematopoietic stem cells (HSCs) and high and regulated hemoglobin expression in the erythroblastic progeny. We developed an erythroid-specific lentiviral vector driving the expression of the human β-globin gene from a minimal promoter/enhancer element containing two hypersensitive sites from the β-globin locus control region. Transplantation of transduced HSCs into thalassemic mice leads to stable and long-term correction of anemia with all red blood cells expressing the transgene. A frequency of 30-50% of transduced HSCs, harboring an average vector copy number per cell of 1, was sufficient to fully correct the thalassemic phenotype. In the mouse model of Cooley's anemia transplantation of transduced cells rescues lethality, leading to either a normal or a thalassemia intermedia phenotype. We show that genetically corrected erythroblasts undergo in vivo selection with preferential survival of progenitors harboring proviral integrations in genome sites more favorable to high levels of vector-derived expression. These data provide a rationale for a gene therapy approach to β-thalassemia based on partially myeloablative transplantation protocols.

Original languageEnglish
Pages (from-to)10547-10552
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number30
Publication statusPublished - Jul 29 2008


  • Gene therapy
  • Hematopoietic stem cells
  • Lentiviral vector

ASJC Scopus subject areas

  • Genetics
  • General


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