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Prepublished online as a Blood First Edition Paper on October 31, 2002; DOI 10.1182/blood-2002-07-2211.
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Blood, 15 March 2003, Vol. 101, No. 6, pp. 2175-2183
GENE THERAPY
The degree of phenotypic correction of murine  -thalassemia
intermedia following lentiviral-mediated transfer of a human  -globin
gene is influenced by chromosomal position effects and vector copy
number
Derek A. Persons,
Phillip W. Hargrove,
Esther R. Allay,
Hideki Hanawa, and
Arthur W. Nienhuis
From the Division of Experimental Hematology,
Department of Hematology and Oncology, St Jude Children's Research
Hospital, Memphis, TN.
Increased fetal hemoglobin (HbF) levels diminish the
clinical severity of  -thalassemia and sickle cell anemia. A
treatment strategy using autologous stem cell-targeted gene transfer
of a  -globin gene may therefore have therapeutic potential. We
evaluated oncoretroviral- and lentiviral-based -globin vectors for
expression in transduced erythroid cell lines. Compared with
-globin, oncoretroviral vectors containing either a -spectrin or
-globin promoter and the  -globin HS40 element, a -globin
lentiviral vector utilizing the -globin promoter and elements from
the -globin locus control region demonstrated a higher
probability of expression. This lentiviral vector design was evaluated
in lethally irradiated mice that received transplants of
transduced bone marrow cells. Long-term, stable erythroid
expression of human -globin was observed with levels of
vector-encoded -globin mRNA ranging from 9% to 19% of total murine
-globin mRNA. The therapeutic efficacy of the vector was subsequently evaluated in a murine model of -thalassemia intermedia. The majority of mice that underwent transplantation expressed significant levels of chimeric m2h2
molecules (termed HbF), the amount of which correlated with the degree
of phenotypic improvement. A group of animals with a mean HbF level of
21% displayed a 2.5 g/dL (25 g/L) improvement in Hb concentration and
normalization of erythrocyte morphology relative to control animals.
-Globin expression and phenotypic improvement was variably lower in
other animals due to differences in vector copy number and chromosomal position effects. These data establish the potential of using a
-globin lentiviral vector for gene therapy of -thalassemia.
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