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Inverse Targeting of Retroviral Vectors: Selective Gene Transfer in a
Mixed Population of Hematopoietic and Nonhematopoietic Cells
Adele K. Fielding,
Marielle Maurice,
Frances J. Morling,
François-Löic Cosset, and
Stephen J. Russell
From the Cambridge Centre for Protein Engineering and Cambridge
University Dept Haematology, MRC Centre, Cambridge, UK; and the Centre
Genetique Moleculaire et Cellulaire, CNRS UMR 5534, Université
Claude-Bernard Lyon-1, Villeurbanne Cedex, France.
We previously reported that retroviral vectors displaying epidermal
growth factor (EGF) as part of a chimeric envelope glycoprotein are
sequestered upon binding to EGF receptor (EGFR)-positive target cells,
leading to loss of infectivity. In the current study, we have displayed
stem cell factor (SCF) on  -galactosidase-transducing ecotropic and amphotropic retroviral vector particles as a factor Xa
protease-cleavable N-terminal extension of the envelope glycoprotein. Viral incorporation of the SCF chimeric envelopes was demonstrated by
immunoblotting of pelleted virions and their specific attachment to Kit
receptors was demonstrated by flow cytometry. Gene transfer studies
showed that when SCF was displayed on an amphotropic envelope, the
infectivity of the SCF-displaying vectors was selectively inhibited on
Kit-expressing cells, but could be restored by adding soluble SCF to
block the Kit receptors or by cleaving the displayed SCF domain from
the vector particles with factor Xa protease. The host range properties
of EGF-displaying and SCF-displaying vectors were then compared in cell
mixing experiments. When EGFR-positive cancer cells and Kit-positive
hematopoietic cells were mixed and exposed to the different engineered
vector particles, the cancer cells were selectively transduced by the
SCF-displaying vector and the hematopoietic cells were selectively
transduced by the EGF-displaying vector. Retroviral display of
polypeptide growth factors can therefore provide the basis for a novel
inverse targeting strategy with potential use for selective
transduction of hematopoietic or nonhematopoietic cells (eg, cancer
cells) in a mixed cell population.
Blood, Vol. 91 No. 5 (March 1), 1998:
pp. 1802-1809
© 1998 by The American Society of Hematology.
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