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Prepublished online as a Blood First Edition Paper on October 31, 2002; DOI 10.1182/blood-2002-07-2211.
Submitted July 23, 2002
Accepted October 24, 2002
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
Division of Experimental Hematology, Department of Hematology and Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA
* Corresponding author; email: derek.persons{at}stjude.org.
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 to -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 (LCR) demonstrated a higher probability of expression. This lentiviral vector design was evaluated in lethally irradiated mice transplanted with transduced bone marrow (BM) cells. Long-term, stable erythroid expression of human -globin was observed with levels of vector-encoded -globin mRNA ranging from 9-19% of total murine -globin mRNA. The therapeutic efficacy of the vector was subsequently evaluated in a murine model of -thalassemia intermedia. The majority of transplanted mice 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 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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