Transcriptional targeting of retroviral vectors to the erythroblastic progeny of transduced hematopoietic stem cells

Alexis Grande, Bianca Piovani, Alessandro Aiuti, Sergio Ottolenghi, Fulvio Mavilio, Giuliana Ferrari

Research output: Contribution to journalArticlepeer-review


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 vital 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 (ΔLNGFR, 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.

Original languageEnglish
Pages (from-to)3276-3285
Number of pages10
Issue number10
Publication statusPublished - May 15 1999

ASJC Scopus subject areas

  • Hematology


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