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Blood, 15 March 2002, Vol. 99, No. 6, pp. 1902-1908
PLENARY PAPER
Successful treatment of murine  -thalassemia intermedia by
transfer of the human -globin gene
Chad May,
Stefano Rivella,
Amy Chadburn, and
Michel Sadelain
From the Department of Human Genetics/Medicine, the
Immunology Program, and the Gene Transfer and Somatic Cell Engineering
Laboratory, Memorial Sloan-Kettering Cancer Center, and the Department
of Pathology, Weill Medical College of Cornell University, New York,
New York.
The  -thalassemias are caused by more than 200 mutations
that reduce or abolish -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 (mu 2:hu ) could be achieved in mice
with -thalassemia intermedia following engraftment with bone marrow cells transduced with a lentiviral vector encoding the human
-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.
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