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.


Reporter: Jill Waalen, M.D.
 


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