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Prepublished online as a Blood First Edition Paper on December 12, 2002; DOI 10.1182/blood-2002-10-3305.
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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 mu 2: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.
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