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Blood, 15 May 2001, Vol. 97, No. 10, pp. 3275-3282
RED CELLS
Functional requirements for phenotypic correction of murine
 -thalassemia: implications for human gene therapy
Derek A. Persons,
Esther R. Allay,
Denise E. Sabatino,
Patrick Kelly,
David M. Bodine, and
Arthur W. Nienhuis
From the Division of Experimental Hematology,
Department of Hematology and Oncology, St Jude Children's Research
Hospital, Memphis, TN; and the Hematopoiesis Section, Genetics and
Molecular Biology Branch, National Institutes of Health, Bethesda, MD.
As initial human gene therapy trials for  -thalassemia are
contemplated, 2 critical questions important to trial design and planning have emerged. First, what proportion of genetically corrected hematopoietic stem cells (HSCs) will be needed to achieve a therapeutic benefit? Second, what level of expression of a transferred globin gene
will be required to improve -thalassemic erythropoiesis? These
questions were directly addressed by means of a murine model of
severe -thalassemia. Generation of -thalassemic mice chimeric for
a minority proportion of genetically normal HSCs demonstrated that
normal HSC chimerism levels as low as 10% to 20% resulted in
significant increases in hemoglobin (Hb) level and diminished extramedullary erythropoiesis. A large majority of the peripheral red
cells in these mice were derived from the small minority of normal
HSCs. In a separate set of independent experiments, -thalassemic mice were bred with transgenic mice that expressed different levels of
human globins. Human  -globin messenger RNA (mRNA) expression at 7%
of the level of total endogenous  -globin mRNA in thalassemic erythroid cells resulted in improved red cell morphology, a greater than 2-g/dL increase in Hb, and diminished reticulocytosis and extramedullary erythropoiesis. Furthermore, -globin mRNA expression at 13% resulted in a 3-g/dL increase in Hb and nearly complete correction of red cell morphology and other indices of inefficient erythropoiesis. These data indicate that a significant therapeutic benefit could be achieved with expression of a transferred globin gene
at about 15% of the level of total -globin mRNA in patients with
severe -thalassemia in whom 20% of erythroid precursors express the
vector genome.
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