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Gene Therapy with Drug Resistance Genes

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Gene Therapy with Drug Resistance Genes Cancer Gene Therapy (2006) 13, 335–345 r 2006 Nature Publishing Group All rights reserved 0929-1903/06 $30.00 www.nature.com/cgt REVIEW Gene therapy with drug resistance genes M Zaboikin1, N Srinivasakumar1 and F Schuening Division of Hematology/Oncology, Department of Medicine, Vanderbilt University, Nashville, TN, USA A major side effect of cancer chemotherapy is myelosuppression. Expression of drug-resistance genes in hematopoietic stem cells (HSC) using gene transfer methodologies holds the promise of overcoming marrow toxicity in cancer chemotherapy. Adequate protection of marrow cells in cancer patients from myelotoxicity in this way would permit the use of escalating doses of chemotherapy for eradicating residual disease. A second use of drug-resistance genes is for coexpression with a therapeutic gene in HSCs to provide a selection advantage to gene-modified cells. In this review, we discuss several drug resistance genes, which are well suited for in vivo selection as well as other newer candidate genes with potential for use in this manner. Cancer Gene Therapy (2006) 13, 335–345. doi:10.1038/sj.cgt.7700912; published online 7 October 2005 Keywords: hematopoietic stem cell; chemoprotection; drug resistance; gene transfer Introduction increasing interest due to their demonstrated superiority to g-retroviral vectors for gene delivery into HSCs.4–7 Hematopoietic stem cells (HSCs) are defined by their Retroviral vectors have been shown to be effective in properties of self-renewal, pluripotency, and life-long correcting genetic disorders in small animal models such persistence following transplantation in the host. HSCs as mice. However, success has been meager in large are easily accessible and deliverable back to recipients by animals including humans. Gene therapy has been well-established transplantation methods. Thus transfer and particularly successful wherein the therapeutic gene expression of drug-resistance genes into HSCs would ensure confers a growth advantage to the gene-modified cells. the protection of not only the stem cells but also their This is exemplified by the remarkable success of gene differentiated progeny. The attributes of HSCs also make transfer of common g-chain cytokine receptor to HSCs in 8–10 them an attractive target for correction of genetic defects in children lacking the relevant gene resulting in SCID. different hematological lineages. For example, HSCs can be The success of gene therapy in SCID patients is attributed used for gene therapy of hemoglobinopathies (thalassemia, to not only improved transduction procedures and sickle-cell anemia) or immune-deficiency disorders (e.g. optimized in vitro culture conditions for HSCs using severe combined immune deficiency or SCID). Drug newer combinations of cytokines, but also to the growth resistance genes are being considered in the latter context advantage conferred to gene-modified lymphoid progeny to provide a mechanism for selection or enrichment of gene- by the particular therapeutic gene used (g-chain of T-cell modified cells to improve the efficacy of gene therapy. The receptor). Similar success has not been forthcoming for reader is referred to several recent reviews1–3 for additional other diseases such as mucopolysaccharidosis or thalasse- information not covered in detail here. mia, where there is no growth advantage for gene- modified cells and the level of marked cells in the peripheral blood of transplanted large animals or humans is rather low to begin with. This can be explained by Gene delivery into HSC inefficient gene transfer into HSCs or poor engraftment of transduced long-term repopulating HSCs. In order to permanently mark or modify HSCs, most Engraftment can be improved by eliminating the investigators use retroviral vectors since they have the endogenous, nontransduced HSCs by treatment of the ability to integrate into the host cell genome. g-retroviral recipient with myeloablative or myelosuppressive doses of vectors have been extensively used for this purpose but total body irradiation or chemotherapeutic agents prior to more recently, lentivirus-based vectors have gathered transplantation of the transduced stem cells. This approach has the disadvantage, that it does not affect Correspondence: Professor FG Schuening, Division of Hematology/ the nontransduced stem cells in the transplant. The Oncology, Department of Medicine, Vanderbilt University, 777 PRB, 2220 Pierce Avenue, Nashville, TN 37232, USA. nontransduced HSCs in the transplant, which usually E-mail: [email protected] outnumber the transduced HSCs, have the advantage in 1These authors contributed equally to this review. engraftment. Elimination of nontransduced cells by Received 18 May 2005; revised 8 August 2005; accepted 12 August selection exvivo prior to transplant, although attractive, 2005; published online 7 October 2005 has its disadvantages. Selection of gene-modified cells Gene therapy with drug resistance genes M Zaboikin et al 336 requires further exvivo manipulation of HSCs following for multidrug resistance (MDR1), multidrug resistance- gene transfer by viral vectors, which in itself requires one associated protein 1 (MRP1), dihydrofolate reductase or more days of culture of HSCs. This would include (DHFR), aldehyde-dehydrogenase (ALDH), glutathione- extra time in culture to obtain a level of transgene S-transferase (GST), cytosine deaminase (CDD) and expression high enough for sorting by flow cytometry (if methylguanine-DNA-methyltransferase (MGMT). Of the marker gene is either expressed on the surface and these, the DHFR, MDR1, MGMT and GST genes available for antibody binding or is a fluorescent protein) (Table 1) have been successfully used for selection of or for drug selection and time of exposure to the drug HSCs in vivo in animal models19–30 and are described in itself. Such increased time in culture has been shown to greater detail below. decrease the number of pluripotent HSCs, thereby compromising long-term engraftment capability.11,12 Therefore, selection of gene-modified cells prior to Dihydrofolate reductase transplant is generally not carried out. In vivo selection of HSCs, in contrast to exvivo Dihydrofolate reductase or DHFR, was the first drug selection, allows the selective outgrowth of transduced resistance gene used for retrovirus vector gene transfer HSCs in their natural environment after transplantation. into murine and canine hematopoietic cells.31,32 This For in vivo selection, a selection gene alone or together protein plays an essential role in thymidilate synthesis by with a potentially therapeutic gene, is introduced into regenerating tetrahydrofolate (Figures 1 and 2). The HSCs. The HSCs are transplanted into the recipient and corresponding selective drugs, methotrexate (MTX) or the appropriate selection agent is administered after the related drug, trimetrexate (TMTX), inhibit the wild- allowing time for the engraftment of the transplant. type enzyme. Several mutants of DHFR have been Engraftment occurs usually around 4 weeks for both identified that are resistant to these drugs.33–35 These murine or canine models. include the leucine to tyrosine substitution at codon 22 The preferential expansion of transduced cells follow- (L22Y) and the phenylalanine to serine substitution at ing transplant can be achieved as follows: (a) by codon 31 (F31S). Double mutations, L22Y and F31S or modifying the HSCs with genes that provide a prolif- L22Y and F31R, of DHFR provide much higher erative or growth advantage; (b) by modifying HSCs with resistance to MTX than each single mutant.36,37 Expres- drug resistance genes that will allow the elimination of sion of mutant DHFR can protect hematopoiesis of nontransduced cells or (c) by using a combination of transplanted mice from the cytotoxic effects of metho- both.13,14 An example of a gene that provides a trexate and trimetrexate.20,21 The advantage of DHFR proliferative advantage is the HoxB4 gene. Expression over other drug-reistance genes, such as MGMT (dis- of this gene increases self-renewal capacity of HSCs and cussed below), is that the drugs used for in vivo selection thereby increases the number of transduced HSCs over of DHFR (MTX and TMTX) are not genotoxic whereas nontransduced HSCs.15–17 Genes that express recombi- the drugs used for selection of MGMT, (BCNU and nant growth factor receptors, containing molecular TMZ) are genotoxic. The major drawback of antifolates switches, that can be controlled by pharmacological as selective agents is their inability to kill resting or inducers which bind to the switches, can also be used noncyling cells. However, cycling cells, such as hemato- for providing proliferative advantage to HSCs. The poietic colony forming progenitors, can also avoid being pharmacological inducers bring about dimerization of killed by anitfolates.38 The reason for MTX or TMTX engineered growth factor receptors resulting in selective not killing these cells is that they express transport expansion of gene-modified HSCs.18 These approaches proteins that allow uptake of extracellular nucleosides for using growth factor receptors will not be discussed further nucleotide synthesis by the salvage pathway, thereby, here. bypassing the need for de novo nucleotide synthesis and thus circumventing antifolate toxicity.39 This necessitates the use of an inhibitor of the nucleoside transport such as In vivo selection using drug-resistance genes nitrobenzylmercaptopurineriboside phosphate (NBMPR- P), to achieve successful in vivo selection
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