A novel murine model of Cooley anemia and its rescue by lentiviral-mediated human β-globin gene transfer Journal Article


Authors: Rivella, S.; May, C.; Chadburn, A.; Rivière, I.; Sadelain, M.
Article Title: A novel murine model of Cooley anemia and its rescue by lentiviral-mediated human β-globin gene transfer
Abstract: Patients affected by β-thalassemia major require lifelong transfusions because of insufficient or absent production of the β chain of hemoglobin (Hb). A minority of patients are cured by allogeneic bone marrow transplantation. In the most severe of the hitherto available mouse models of β-thalassemia, a model for human β-thalassemia intermedia, we previously demonstrated that globin gene transfer in bone marrow cells is curative, stably raising Hb levels from 8.0-8.5 to 11.0-12.0 g/dL in long-term chimeras. To fully assess the therapeutic potential of gene therapy in the context of a lethal anemia, we now have created an adult model of β0-thalassemia major. In this novel model, mice engrafted with β-globin-null (Hbbth3/th3) fetal liver cells succumb to ineffective erythropoiesis within 60 days. These mice rapidly develop severe anemia (2-4 g/dL), massive splenomegaly, extramedullary hematopoiesis (EMH), and hepatic iron overload. Remarkably, most mice (11 of 13) treated by lentivirus-mediated globin gene transfer were rescued. Long-term chimeras with an average 1.0-2.4 copies of the TNS9 vector in their hematopoietic and blood cells stably produced up to 12 g/dL chimeric Hb consisting of muα2:huβ2 tetramers. Pathologic analyses indicated that erythroid maturation was restored, while EMH and iron overload dramatically decreased. Thus, we have established an adult animal model for the most severe of the hemoglobinopathies, Cooley anemia, which should prove useful to investigate both genetic and pharmacologic treatments. Our findings demonstrate the remarkable efficacy of lentivirus-mediated globin gene transfer in treating a fulminant blood disorder and strongly support the efficacy of gene therapy in the severe hemoglobinopathies. © 2003 by The American Society of Hematology.
Keywords: controlled study; human cell; genetics; disease course; nonhuman; animal cell; mouse; animal; cytology; mouse mutant; animals; mice; mice, knockout; gene expression profiling; erythropoiesis; hematopoietic stem cell transplantation; mice, inbred c57bl; gene transfer; c57bl mouse; gene vector; genetic transduction; genetic vectors; transduction, genetic; chimera; disease model; prenatal development; blood; liver; disease severity; feasibility study; hybrid protein; recombinant fusion proteins; feasibility studies; gene therapy; globin; beta thalassemia; blood transfusion; beta-thalassemia; blood cell; hematopoiesis; bone marrow cell; disease models, animal; bone marrow transplantation; bioavailability; lentivirinae; globins; lethal gene; genes, lethal; thalassemia major; maturation; cross breeding; crosses, genetic; iron overload; dna vector; humans; human; male; female; priority journal; article; radiation chimera
Journal Title: Blood
Volume: 101
Issue: 8
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2003-08-15
Start Page: 2932
End Page: 2939
Language: English
DOI: 10.1182/blood-2002-10-3305
PUBMED: 12480689
PROVIDER: scopus
DOI/URL:
Notes: Export Date: 12 September 2014 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Chad May
    21 May
  2. Stefano Rivella
    16 Rivella
  3. Michel W J Sadelain
    456 Sadelain
  4. Isabelle C Riviere
    164 Riviere