Progress
in Stem-Cell Drug Resistance-Gene Therapy: Current and Future Applications
Stanton
L. Gerson, M.D.
University Hospitals of Cleveland and Case Western Reserve
University, Cleveland, Ohio, USA
Summary:
Therapy to insert drug-resistant genes into blood cell progenitors
may enable use of higher chemotherapy doses by preventing bone marrow
suppression. Trials introduce the multidrug resistance gene (MDR-1)
into CD34+ cells used in autologous bone marrow transplantation. Researchers
work to improve gene delivery and expression, as well as selection
of progenitor cells that will maintain proliferation of transferred
genes.
Therapy to protect blood cell progenitors by inserting genes for
drug resistance may enable use of higher chemotherapy doses by preventing
the side effect of bone marrow suppression. Several approaches for
inserting drug-resistance genes into stem cells, which are subsequently
transfused into bone marrow, are being tested. Problems with gene
delivery and expression, as well as appropriate progenitor cell
selection, remain.
Dr. Gerson reviewed clinical trials introducing the multidrug resistance
gene (MDR-1) into CD34+ cells used in autologous bone marrow transplants.
The MDR-1 gene encodes a transmembrane protein that pumps agents,
including anthracyclines, vincristine, etoposide, and paclitaxel,
out of cells. Modified retroviruses were used for gene insertion
in all trials. Maintenance gene expression after transfusion has
been limited.
Better results have been achieved using cytokines-- including granulocyte-colony
stimulating factor, stem cell factor, and megakaryocyte growth and
development factor to enhance gene incorporation. Cytokines stimulate
the cell division required for effective gene integration. In one
trial, up to 27% of bone marrow cells had evidence of MDR-1 provirus
in the genome 30 days after transfusion, with 10% after one year.
Clinical trials are planned for stem cell transduction with other
drug-resistance genes. It is hoped that use of cytokines, targeting
of earlier progenitors, and use of more efficient delivery systems,
such as lentiviruses instead of retroviruses, will improve the efficacy
of stem cell protection with these and other drug-resistance genes.