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Prepublished online as a Blood First Edition Paper on December 12, 2002; DOI 10.1182/blood-2002-10-3305. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-10-3305v1 101/8/2932    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Rivella, S. Articles by Sadelain, M. Search for Related Content PubMed PubMed Citation Articles by Rivella, S. Articles by Sadelain, M. Related Collections Red Cells Plenary Papers Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 April 2003, Vol. 101, No. 8, pp. 2932-2939 PLENARY PAPER A novel murine model of Cooley anemia and its rescue by lentiviral-mediated human -globin gene transfer Stefano Rivella, Chad May, Amy Chadburn, Isabelle Rivière, and Michel Sadelain From the Department of Human Genetics/Medicine, the Gene Transfer and Somatic Cell Engineering Laboratory, and the Immunology Program, Memorial Sloan-Kettering Cancer Center; and the Department of Pathology, Weill Medical College, Cornell University, New York, NY. Patients affected by -thalassemia major require lifelong transfusions because of insufficient or absent production of the  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 -thalassemia, a model for human -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 0-thalassemia major. In this novel model, mice engrafted with -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 mu2:hu2 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.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. W. Nienhuis Development of gene therapy for blood disorders Blood, May 1, 2008; 111(9): 4431 - 4444. [Abstract] [Full Text] [PDF] P. Moi and M. 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