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Blood, Vol. 93 No. 10 (May 15), 1999:
pp. 3276-3285
Transcriptional Targeting of Retroviral Vectors to the Erythroblastic
Progeny of Transduced Hematopoietic Stem Cells
Alexis Grande,
Bianca Piovani,
Alessandro Aiuti,
Sergio Ottolenghi,
Fulvio Mavilio, and
Giuliana Ferrari
From TIGET, Istituto Scientifico H.S. Raffaele, Milano, Italy; and
the Department of Genetics, University of Milano, Milano, Italy.
Targeted expression to specific tissues or cell lineages is a
necessary feature of a gene therapy vector for many clinical applications, such as correction of hemoglobinopathies or thalassemias by transplantation of genetically modified hematopoietic stem cells. We
developed retroviral vectors in which the constitutive viral enhancer
in the U3 region of the 3' LTR is replaced by an autoregulatory
enhancer of the erythroid-specific GATA-1 transcription factor gene.
The replaced enhancer is propagated to the 5' LTR upon
integration into the target cell genome. The modified vectors were used
to transduce human hematopoietic cell lines, cord blood-derived CD34+ stem/progenitor cells, and murine bone marrow
repopulating stem cells. The expression of appropriate reporter genes
( LNGFR, EGFP) was analyzed in the differentiated progeny of
transduced stem cells in vitro, in liquid culture as well as in
clonogenic assay, and in vivo, after bone marrow transplantation in
lethally irradiated mice. The GATA-1 autoregulatory enhancer
effectively restricts the expression of the LTR-driven proviral
transcription unit to the erythroblastic progeny of both human
progenitors and mouse-repopulating stem cells. Packaging of viral
particles, integration into the target genome, and stability of the
integrated provirus are not affected by the LTR modification. Enhancer
replacement is therefore an effective strategy to target expression of
a retroviral transgene to a specific progeny of transduced
hematopoietic stem cells.
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