Successful treatment of murine β-thalassemia intermedia by transfer of the human β-globin gene Journal Article


Authors: May, C.; Rivella, S.; Chadburn, A.; Sadelain, M.
Article Title: Successful treatment of murine β-thalassemia intermedia by transfer of the human β-globin gene
Abstract: The β-thalassemias are caused by more than 200 mutations that reduce or abolish β-globin production. The severity of the resulting anemia can lead to lifelong transfusion dependency. A genetic treatment based on globin gene transfer would require that transgene expression be erythroid specific, elevated, and sustained over time. We report here that long-term synthesis of chimeric hemoglobin (muα2:huβ2 A) could be achieved in mice with β-thalassemia intermedia following engraftment with bone marrow cells transduced with a lentiviral vector encoding the human β-globin gene. In the absence of any posttransduction selection, the treated chimeras exhibit durably increased hemoglobin levels without diminution over 40 weeks. Ineffective erythropoiesis and extramedullary hematopoiesis (EMH) regress, as reflected by normalization of spleen size, architecture, hematopoietic colony formation, and disappearance of liver EMH. These findings establish that a sustained increase of 3 to 4 g/dL hemoglobin is sufficient to correct ineffective erythropoiesis. Hepatic iron accumulation is markedly decreased in 1-year-old chimeras, indicating persistent protection from secondary organ damage. These results demonstrate for the first time that viral-mediated globin gene transfer in hematopoietic stem cells effectively treats a severe hemoglobin disorder. © 2002 by The American Society of Hematology.
Keywords: controlled study; treatment outcome; gene mutation; nonhuman; animals; mice; animal tissue; bone marrow cells; gene expression; erythropoiesis; animal experiment; animal model; hematopoietic stem cell transplantation; gene transfer; viral gene delivery system; genetic transduction; transduction, genetic; chimera; disease severity; genetic transfection; recombinant fusion proteins; cell culture; splenomegaly; gene therapy; lentivirus vector; beta thalassemia; blood transfusion; transgene; beta-thalassemia; hematopoietic stem cells; bone marrow cell; bone marrow transplantation; genetic code; globins; beta globin; spleen size; extramedullary hematopoiesis; iron overload; hemoglobin determination; iron storage; humans; male; female; priority journal; article; hematopoiesis, extramedullary
Journal Title: Blood
Volume: 99
Issue: 6
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2002-03-15
Start Page: 1902
End Page: 1908
Language: English
DOI: 10.1182/blood.V99.6.1902
PUBMED: 11877258
PROVIDER: scopus
DOI/URL:
Notes: Export Date: 14 November 2014 -- Source: Scopus
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MSK Authors
  1. Chad May
    21 May
  2. Stefano Rivella
    16 Rivella
  3. Michel W J Sadelain
    541 Sadelain