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Blood, 1 November 2001, Vol. 98, No. 9, pp. 2664-2672
GENE THERAPY
High-level erythroid-specific gene expression in primary human
and murine hematopoietic cells with self-inactivating lentiviral
vectors
Francois Moreau-Gaudry,
Ping Xia,
Gang Jiang,
Natalya P. Perelman,
Gerhard Bauer,
James Ellis,
Katherine H. Surinya,
Fulvio Mavilio,
Che-Kun Shen, and
Punam Malik
From the Children's Hospital Los Angeles, University
of Southern California School of Medicine, Los Angeles; University of
Bordeaux, Bordeaux, France; Developmental Biology, Hospital for Sick
Children, Toronto, Ontario, Canada; University of Adelaide, Adelaide,
Australia; TIGET, Instituto Scientifico H.S. Raffaele, Milan, Italy;
Department of Biomedical Sciences, University of Modena School of
Medicine, Modena, Italy; and Academic Sinica, Nankang, Taipei, Taiwan,
Republic of China.
Use of oncoretroviral vectors in gene therapy for
hemoglobinopathies has been impeded by low titer vectors, genetic
instability, and poor expression. Fifteen self- inactivating (SIN)
lentiviral vectors using 4 erythroid promoters in combination with 4 erythroid enhancers with or without the woodchuck hepatitis virus
postregulatory element (WPRE) were generated using the enhanced green
fluorescent protein as a reporter gene. Vectors with high
erythroid-specific expression in cell lines were tested in primary
human CD34+ cells and in vivo in the murine bone marrow
(BM) transplantation model. Vectors containing the ankyrin-1 promoter
showed high-level expression and stable proviral transmission. Two
vectors containing the ankyrin-1 promoter and 2 erythroid enhancers
(HS-40 plus GATA-1 or HS-40 plus 5-aminolevulinate synthase intron 8 [I8] enhancers) and WPRE expressed at levels higher than the
HS2/ -promoter vector in bulk unilineage erythroid cultures and
individual erythroid blast-forming units derived from human BM
CD34+ cells. Sca1+/lineage Ly5.1
mouse hematopoietic cells, transduced with these 2 ankyrin-1 promoter
vectors, were injected into lethally irradiated Ly5.2 recipients.
Eleven weeks after transplantation, high-level expression was seen from
both vectors in blood (63%-89% of red blood cells) and erythroid
cells in BM (70%-86% engraftment), compared with negligible
expression in myeloid and lymphoid lineages in blood, BM, spleen, and
thymus (0%-4%). The I8/HS-40-containing vector encoding a hybrid
human / -globin gene led to 43% to 113% human -globin expression/copy of the mouse  -globin gene. Thus,
modular use of erythroid-specific enhancers/promoters and WPRE in
SIN-lentiviral vectors led to identification of high-titer, stably
transmitted vectors with high-level erythroid-specific expression for
gene therapy of red cell diseases.
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