Gene therapy to protect haematopoietic cells from cytotoxic cancer drugs

Nature Reviews Cancer

Volumn 2, Issue 6, 2002, Pages 431-441

  Sorrentino, Brian P ^a  

^a ST JUDE CHILDREN S RESEARCH HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; CARMUSTINE; CHLOROETHYLNITROSOUREA; DIHYDROFOLATE REDUCTASE; DOXORUBICIN; ENVELOPE PROTEIN; GENE PRODUCT; METHOTREXATE; METHYLGUANINE METHYLTRANSFERASE; MULTIDRUG RESISTANCE PROTEIN 1; NITROBENZYLTHIOINOSINE; PACLITAXEL; RETROVIRUS VECTOR; TEMOZOLOMIDE; TRIMETREXATE; UNCLASSIFIED DRUG; VINBLASTINE;

AMINO ACID SUBSTITUTION; AUTOTRANSPLANTATION; BONE MARROW SUPPRESSION; BRAIN TUMOR; BREAST CARCINOMA; CANCER; CANCER CHEMOTHERAPY; CELL PROTECTION; CELL TRANSPLANTATION; CLINICAL TRIAL; EXPRESSION VECTOR; GASTROINTESTINAL TOXICITY; GENE EXPRESSION; GENE THERAPY; GENETIC TRANSDUCTION; HEMATOPOIETIC CELL; HEMATOPOIETIC STEM CELL; HUMAN; MAXIMUM ALLOWABLE CONCENTRATION; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; VIRUS ADSORPTION; VIRUS GENOME; VIRUS REPLICATION; ADENOVIRUS; ANIMAL; CELL SURVIVAL; DRUG EFFECT; DRUG RESISTANCE; FORECASTING; GENE VECTOR; MOUSE; PHYSIOLOGY; RETROVIRUS;

ADENOVIRIDAE; ANIMALS; ANTINEOPLASTIC AGENTS; CELL SURVIVAL; CLINICAL TRIALS; DRUG RESISTANCE, NEOPLASM; FORECASTING; GENE THERAPY; GENETIC VECTORS; HEMATOPOIETIC STEM CELLS; HUMANS; MICE; RETROVIRIDAE;

EID: 0036594445     PISSN: 1474175X     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrc823     Document Type: Review

References (110)

1. Gottesman, M. M. Mechanisms of cancer drug resistance. Annu. Rev. Med. 53, 615-627 (2002).
2. Gottesman, M. M., Fojo, T. & Bates, S. E. Multidrug resistance in cancer: role of ATP-dependent transporters. Nature Rev. Cancer 2, 48-58 (2002). A review of the molecular mechanisms of drug resistance, with a focus on the ABC transporter superfamily.
3. Lee, C. G., Vieira, W. D., Pastan, I. & Gottesman, M. M. An episomally maintained MDR1 gene for gene therapy. Hum. Gene Ther. 12, 945-953 (2001).
4. Kimchi-Sarfaty, C., Nun-Shaul, O., Rund, D., Oppenheim, A. & Gottesman, M. M. In vitro-packaged SV40 pseudovirions as highly efficient vectors for gene transfer. Hum. Gene Ther. 13, 299-310 (2002).
5. Baudard, M. et al. Expression of the human multidrug resistance and glucocerebrosidase cDNAs from adeno-associated vectors: efficient promoter activity of AAV sequences and in vivo delivery via liposomes. Hum. Gene Ther. 7, 1309-1322 (1996).
6. Lemischka, I. R., Raulet, D. H. & Mulligan, R. C. Developmental potential and dynamic behavior of hematopoietic stem cells. Cell 45, 917-927 (1986).
7. Dick, J. E., Magli, M. C., Huszar, D., Phillips, R. A. & Bernstein, A. Introduction of a selectable gene into primitive stem cells capable of long-term reconstitution of the hemopoietic system of W/Wv mice. Cell 42, 71-79 (1985). The first demonstration that retroviral vectors can be used to stably insert foreign genetic material in long-term reconstituting stem cells. This work formed the basis for using retroviral vectors for haematopoietic gene therapy.
8. Williams, D. A., Lemischka, I. R., Nathan, D. G. & Mulligan, R. C. Introduction of new genetic material into pluripotent haematopoietic stem cells of the mouse. Nature 310, 476-480 (1984).
9. Persons, D. A. et al. Retroviral-mediated transfer of the green fluorescent protein gene into murine hematopoietic cells facilitates scoring and selection of transduced progenitors in vitro and identification of genetically modified cells in vivo. Blood 90, 1777-1786 (1997).
10. Persons, D. A. et al. Utilization of the green flourescent protein gene as a marker to identify and track genetically-modified hematopoietic cells. Nature Med. 4, 1201-1205 (1998).
11. Tisdale, J. F. et al. Ex vivo expansion of genetically marked rhesus peripheral blood progenitor cells results in diminished long-term repopulating ability. Blood 92, 1131-1141 (1998). Using a modern gene-transfer protocol in non-human primates, this study showed that up to 20% of blood cells could be transduced with a retroviral vector. This provided the first evidence that retroviral vectors could be used to obtain a therapeutically relevant number of transduced cells.
12. Dunbar, C. E. et al. Improved retroviral gene transfer into murine and Rhesus peripheral blood or bone marrow repopulating cells primed in vivo with stem cell factor and granulocyte colony-stimulating factor. Proc. Natl Acad. Sci. USA 93, 11871-11876 (1996).
13. Dunbar, C. E. et al. Retrovirally marked CD34-enriched peripheral blood and bone marrow cells contribute to long-term engraftment after autologous transplantation. Blood 85, 3048-3057 (1995).
14. Kiem, H. P. et al. Gene transfer into marrow repopulating cells: comparison between amphotropic and gibbon ape leukemia virus pseudotyped retroviral vectors in a competitive repopulation assay in baboons. Blood 90, 4638-4645 (1997).
15. Kiem, H. R. et al. Improved gene transfer into baboon marrow repopulating cells using recombinant human fibronectin fragment CH-296 in combination with interleukin-6, stem cell factor, FLT-3 ligand, and megakaryocyte growth and development factor. Blood 92, 1878-1886 (1998).
16. Kim, J. W., Closs, E. I., Albritton, L. M. & Cunningham, J. M. Transport of cationic amino acids by the mouse ecotropic retrovirus receptor. Nature 352, 725-728 (1991).
17. Orlic, D. et al. The level of mRNA encoding the amphotropic retrovirus receptor in mouse and human hematopoietic stem cells is low and correlates with the efficiency of retrovirus transduction. Proc. Natl Acad. Proc. Sci. USA 93, 11097-11102 (1996). This study showed the importance of selecting the appropriate retroviral envelope in designing gene-therapy vectors. The authors showed that haematopoietic stem cells express very low levels of a commonly used envelope receptor.
18. Miller, D. G., Edwards, R. H. & Miller, A. D. Cloning of the cellular receptor for amphotropic murine retroviruses reveals homology to that for gibbon ape leukemia virus. Proc. Natl Acad. Sci. USA 91, 78-82 (1994).
19. Orlic, D. et al. Identification of human and mouse hematopoietic stem cell populations expressing high levels of mRNA encoding retrovirus receptors. Blood 91, 3247-3264 (1998).
20. Kavanaugh, M. P. et al. Cell-surface receptors for gibbon ape leukemia virus and amphotropic murine retrovirus are inducible sodium-dependent phosphate symporters. Proc. Natl Acad. Sci. USA 91, 7071-7075 (1994).
21. Rasko, J. E., Battini, J. L., Gottschalk, R. J., Mazo, I. & Miller, A. D. The RD114/simian type D retrovirus receptor is a neutral amino acid transporter. Proc. Natl Acad. Sci. USA 96, 2129-2134 (1999).
22. Porter, C. D. et al. Comparison of efficiency of infection of human gene therapy target cells via four different retroviral receptors. Hum. Gene Ther. 7, 913-919 (1996).
23. Kelly, P. F., Vandergriff, J., Nathwani, A., Nienhuis, A. W. & Vanin, E. F. Highly efficient gene transfer into cord blood nonobese diabetic/severe combined immunodeficiency repopulating cells by oncoretroviral vector particles pseudotyped with the feline endogenous retrovirus (RD114) envelope protein. Blood 96, 1206-1214 (2000).
24. Emi, N., Friedmann, T. & Yee, J. K. Pseudotype formation of murine leukemia virus with the G protein of vesicular stomatitis virus. J. Virol. 65, 1202-1207 (1991).
25. + cells that mediate long-term engraftment of NOD/SCID mice by HIV vectors. Science 283, 682-686 (1999). This study reported the use of HIV-based lentiviral vectors to transduce human stem cells, and shows efficient transduction in an immunodeficient mouse model of reconstitution.
26. Barrette, S. et al. Superior transduction of mouse hematopoietic stem cells with 10A1 and VSV-G pseudotyped retrovirus vectors. Mol. Ther. 1, 330-338 (2000).
27. Hanawa, H. et al. Comparison of various envelope proteins for their ability to pseudotype lentiviral vectors and transduce primitive hematopoietic cells from human blood. Mol. Ther. 5, 242-251 (2002).
28. + cells. Exp. Hematol. 24, 738-747 (1996).
29. Moebes, A. et al. Human foamy virus reverse transcription that occurs late in the viral replication cycle. J. Virol. 71, 7305-7311 (1997).
30. Vassilopoulos, G., Trobridge, G., Josephson, N. C. & Russell, D. W. Gene transfer into murine hematopoietic stem cells with helper-free foamy virus vectors. Blood 98, 604-609 (2001).
31. Hirata, R. K., Miller, A. D., Andrews, R. G. & Russell, D. W. Transduction of hematopoietic cells by foamy virus vectors. Blood 88, 3654-3661 (1996).
32. Miller, D. G., Adam, M. A. & Miller, A. D. Gene transfer by retrovirus vectors occurs only in cells that are actively replicating at the time of infection. Mol. Cell Biol. 10, 4239-4242 (1990).
33. Cheshier, S. H., Morrison, S. J., Liao, X. & Weissman, I. L. In vivo proliferation and cell cycle kinetics of long-term self-renewing hematopoietic stem cells. Proc. Natl Acad. Sci. USA 96, 3120-3125 (1999).
34. Bodine, D. M., Karlsson, S. & Nienhuis, A. W. Combination of interleukins 3 and 6 preserves stem cell function in culture and enhances retrovirus-mediated gene transfer into hematopoietic stem cells. Proc. Natl Acad. Sci. USA 86, 8897-8901 (1989).
35. Bhatia, M. et al. Quantitative analysis reveals expansion of human hematopoietic repopulating cells after short-term ex vivo culture. J. Exp. Med. 186, 619-624 (1997).
36. Dao, M. A., Taylor, N. & Nolta, J. A. Reduction in levels of the cyclin-dependent kinase inhibitor p27(kip1) coupled with transforming growth factor-β neutralization induces cell-cycle entry and increases retroviral transduction of primitive human hematopoietic cells. Proc. Natl Acad. Sci. USA 95, 13006-13011 (1998).
37. Lewis, P. F. & Emerman, M. Passage through mitosis is required for oncoretroviruses but not for the human immunodeficiency virus. J. Virol. 68, 510-516 (1994).
38. Uchida, N. et al. HIV, but not murine leukemia virus, vectors mediate high efficiency gene transfer into freshly isolated G0/G1 human hematopoietic stem cells. Proc. Natl Acad. Sci. USA 95, 11939-11944 (1998).
39. Bukrinsky, M. I. et al. A nuclear localization signal within HIV-1 matrix protein that governs infection of non-dividing cells. Nature 365, 666-669 (1993).
40. Fletcher, T. M. et al. Nuclear import and cell cycle arrest functions of the HIV-1 Vpr protein are encoded by two separate genes in HIV-2/SIV(SM). EMBO J. 15, 6155-6165 (1996).
41. Walters, M. C. et al. Transcriptional enhancers act in cis to suppress position-effect variegation. Genes Dev. 10, 185-195 (1996).
42. Francastel, C., Walters, M. C., Groudine, M. & Martin, D. I. A functional enhancer suppresses silencing of a transgene and prevents its localization close to centrometric heterochromatin. Cell 99, 259-269 (1999).
43. Emery, D. W., Yannaki, E., Tubb, J. & Stamatoyannopoulos, G. A chromatin insulator protects retrovirus vectors from chromosomal position effects. Proc. Natl Acad. Sci. USA 97, 9150-9155 (2000).
44. Walters, M. C. et al. The chicken β-globin 5′HS4 boundary element blocks enhancer-mediated suppression of silencing. Mol. Cell Biol. 19, 3714-3726 (1999).
45. Knipper, R. et al. Improved post-transcriptional processing of an MDR1 retrovirus elevates expression of multidrug resistance in primary human hematopoietic cells. Gene Ther. 8, 239-246 (2001).
46. Schambach, A. et al. Context dependence of different modules for posttranscriptional enhancement of gene expression from retroviral vectors. Mol. Ther. 2, 435-445 (2000).
47. Hildinger, M., Abel, K. L., Ostertag, W. & Baum, C. Design of 5′ untranslated sequences in retroviral vectors developed for medical use. J. Virol. 73, 4083-4089 (1999).
48. Robbins, P. B. et al. Consistent, persistent expression from modified retroviral vectors in murine hematopoietic stem cells. Proc. Natl Acad. Sci. USA 95, 10182-10187 (1998).
49. Hawley, R. G., Lieu, F. H., Fong, A. Z. & Hawley, T. S. Versatile retroviral vectors for potential use in gene therapy. Gene Ther. 1, 136-138 (1994).
50. Mickisch, G. H., Licht, T., Merlino, G. T., Gottesman, M. M. & Pastan, I. Chemotherapy and chemosensitization of transgenic mice which express the human multidrug resistance gene in bone marrow: efficacy, potency, and toxicity. Cancer Res. 51, 5417-5424 (1991).
51. Sorrentino, B. P. et al. Selection of drug-resistant bone marrow cells in vivo after retroviral transfer of human MDR1. Science 257, 99-103 (1992). An MDR1-expressing retroviral vector was shown to protect mice against the myelosuppressive effects of taxol. Furthermore, taxol treatment was shown to promote in vivo selection of transduced stem cells.
52. Podda, S. et al. Transfer and expression of the human multiple drug resistance gene into live mice. Proc. Natl Acad. Sci. USA 89, 9676-9680 (1992).
53. Licht, T. et al. Drug selection with paclitaxel restores expression of linked IL-2 receptor γ-chain and multidrug resistance (MDR1) transgenes in canine bone marrow. Proc. Natl Acad. Sci. USA 99, 3123-3128 (2002).
54. Cardarelli, C. O., Aksentijevich, I., Pastan, I. & Gottesman, M. M. Differential effects of P-glycoprotein inhibitors on NIH3T3 cells transfected with wild-type (G185) or mutant (V185) multidrug transporters. Cancer Res. 55, 1086-1091 (1995).
55. Hafkemeyer, P., Licht, T., Pastan, I. & Gottesman, M. M. Chemoprotection of hematopoietic cells by a mutant P-glycoprotein resistant to a potent chemosensitizer of multidrug-resistant cancers. Hum. Gene Ther. 11, 555-565 (2000).
56. Sorrentino, B. P., McDonagh, K. T., Woods, D. & Orlic, D. Expression of retroviral vectors containing the human multidrug resistance 1 cDNA in hematopoietic cells of transplanted mice. Blood 86, 491-501 (1995).
57. Galipeau, J., Benaim, E., Spencer, H. T., Blakley, R. L. & Sorrentino, B. P. A bicistronic retroviral vector for protecting hematopoietic cells against antifolates and P-glycoprotein effluxed drugs. Hum. Gene Ther. 8,1773-1783 (1997).
58. Bunting, K. D., Galipeau, J., Topham, D., Benaim, E. & Sorrentino, B. P. Transduction of murine bone marrow cells with an MDR1 vector enables ex vivo stem cell expansion, but these expanded grafts cause a myeloproliferative syndrome in transplanted mice. Blood 92, 2269-2279 (1998).
59. Bunting, K. D., Zhou, S., Lu, T. & Sorrentino, B. P. Enforced P-glycoprotein pump function in murine bone marrow cells results in expansion of side population stem cells in vitro and repopulating cells in vivo. Blood 96, 902-909 (2000).
60. Johnstone, R. W., Cretney, E. & Smyth, M. J. P-glycoprotein protects leukemia cells against caspase-dependent, but not caspase-independent, cell death. Blood 93, 1075-1085 (1999).
61. Smyth, M. J., Krasovskis, E., Sutton, V. R. & Johnstone, R. W. The drug efflux protein, P-glycoprotein, additionally protects drug-resistant tumor cells from multiple forms of caspase-dependent apoptosis. Proc. Natl Acad. Sci. USA 95, 7024-7029 (1998).
62. Sellers, S. E. et al. The effect of multidrug-resistance 1 gene versus neo transduction on ex vivo and in vivo expansion of rhesus macaque hematopoietic repopulating cells. Blood 97, 1888-1891 (2001).
63. Williams, D. A., Hsieh, K., DeSilva, A. & Mulligan, R. C. Protection of bone marrow transplant recipients from lethal doses of methotrexate by the generation of methotrexate-resistant bone marrow. J. Exp. Med. 166, 210-218 (1987).
64. Simonsen, C. C. & Levinson, A. D. Isolation and expression of an altered mouse dihydrofolate reductase cDNA. Proc. Natl Acad. Sci. USA 80, 2495-2499 (1983).
65. Lewis, W. S. et al. Methotrexate-resistant variants of human dihydrofolate reductase with substitutions of leucine 22. Kinetics, crystallography, and potential as selectable markers. J. Biol. Chem. 270, 5057-5064 (1995).
66. Chunduru, S. K. et al. Methotrexate-resistant variants of human dihydrofolate reductase. Effects of Phe31 substitutions. J. Biol. Chem. 269, 9547-9555 (1994).
67. Blakley, R. L. & Sorrentino, B. P. In vitro mutations in dihydrofolate reductase that confer resistance to methotrexate: potential for clinical application. Hum. Mut. 11, 259-263 (1998).
68. Corey, C. A., DeSilva, A. D., Holland, C. A. & Williams, D. A. Serial transplantation of methotrexate-resistant bone marrow: protection of murine recipients from drug toxicity by progeny of transduced stem cells. Blood 75, 337-343 (1990).
69. Spencer, H. T., Sleep, S. E., Rehg, J. E., Blakley, R. L. & Sorrentino, B. P. A gene transfer strategy for making bone marrow cells resistant to trimetrexate. Blood 87, 2579-2587 (1996).
70. Zhao, S. C., Banerjee, D., Mineishi, S. & Bertino, J. R. Post-transplant methotrexate administration leads to improved curability of mice bearing a mammary tumor transplanted with marrow transduced with a mutant human dihydrofolate reductase cDNA. Hum. Gene Ther. 8, 903-909 (1997).
71. + peripheral blood progenitor cells after introduction of a mutated dihydrofolate reductase cDNA via retroviral gene transfer. Blood 85, 566-574 (1995).
72. Flasshove, M., Banerjee, D., Bertino, J. R. & Moore, M. A. Increased resistance to methotrexate in human hematopoietic cells after gene transfer of the Ser31 DHFR mutant. Leukemia 9 (Suppl. 1), S34-S37 (1995).
73. Allay, J. A. et al. Sensitization of hematopoietic stem and progenitor cells to trimetrexate using nucleoside transport inhibitors. Blood 90, 3546-3554 (1997).
74. Allay, J. A. et al. In vivo selection of retrovirally transduced hematopoietic stem cells. Nature Med. 4, 1136-1143 (1998). Formal proof that a drug-resistance vector can promote in vivo selection of haematopoietic stem cells in mice. This was done using a DHFR resistance vector and a novel antifolate regimen.
75. May, C., Gunther, R. & McIvor, R. S. Protection of mice from lethal doses of methotrexate by transplantation with transgenic marrow expressing drug-resistant dihydrofolate reductase activity. Blood 86, 2439-2448 (1995).
76. Takebe, N. et al. Generation of dual resistance to 4-hydroperoxycyclophosphamide and methotrexate by retroviral transfer of the human aldehyde dehydrogenase class 1 gene and a mutated dihydrofolate reductase gene. Mol. Ther. 3, 88-96 (2001).
77. Erickson, L. C., Laurent, G., Sharkey, N. A. & Kohn, K. W. DNA cross-linking and monoadduct repair in nitrosourea-treated human tumour cells. Nature 288, 727-729 (1980).
78. Brent, T. P. et al. Repair of O-alkylpyrimidines in mammalian cells: a present consensus. Proc. Natl Acad. Sci. USA 85, 1759-1762 (1988).
79. Middlemas, D. S. et al. Biochemical correlates of temozolomide sensitivity in pediatric solid tumor xenograft models. Clin. Cancer Res. 6, 998-1007 (2000).
80. 6-benzylguanine plus BCNU. Blood 88, 1649-1655 (1996).
81. 6-benzylguanine. Biochemistry 32, 11998-12006 (1993).
82. 6-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in a human colon cancer xenograft completely resistant to BCNU alone. Biochem. Pharmacol. 45, 483-491 (1993).
83. 6-benzylguanine for patients undergoing surgery for malignant glioma. J. Clin. Oncol. 16, 3570-3575 (1998).
84. 6-benzylguanine: a clinical trial establishing the biochemical modulatory dose in tumor tissue for alkyltransferase-directed DNA repair. Cancer Res. 59, 2402-2410 (1999).
85. 6-benzylguanine potentiates the in vivo toxicity and clastogenicity of temozolomide and BCNU in mouse bone marrow. Blood 89, 1566-1573 (1997).
86. 6-benzylguanine increases the sensitivity of human primary bone marrow cells to the cytotoxic effects of temozolomide. Exp. Hematol. 23, 112-116 (1995).
87. 6-benzylguanine in oligodeoxyribonucleotides. J. Biol. Chem. 273, 10863-10867 (1998).
88. 6-methylguanine-DNA methyltransferase mutants: implications for drug resistance gene therapy. Hum. Gene Ther. 10, 2769-2778 (1999).
89. 6-benzylguanine sensitization to chloroethylnitrosourea treatment. J. Pharmacol. Exp. Ther. 290, 1467-1474 (1999).
90. 6-benzylguanine plus 1,3-bis(2-chloroethyl)-1-nitrosourea. Proc. Natl Acad. Sci. USA 93, 14088-14093 (1996).
91. 6-methylguanine DNA methyltransferase complementary DNA. J. Immunol. 158, 1006-1013 (1997).
92. Moritz, T., Mackay, W., Glassner, B. J., Williams, D. A. & Samson, L. Retrovirus-mediated expression of a DNA repair protein in bone marrow protects hematopoietic cells from nitrosourea-induced toxicity in vitro and in vivo. Cancer Res. 55, 2608-2614 (1995).
93. 6-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea. Cancer Res. 57, 5093-5099 (1997).
94. Allay, J. A., Dumenco, L. L., Koc, O. N., Liu, L. & Gerson, S. L. Retroviral transduction and expression of the human alkyltransferase CDNA provides nitrosourea resistance to hematopoietic cells. Blood 85, 3342-3351 (1995).
95. 6-benzylguanine, and an alkyltransferase-expressing retroviral vector. Mol. Ther. 3, 78-87 (2001).
96. 6-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea and allows intensive therapy of 1,3-bis(2-chloroethyl)-1-nitrosourea-resistant human colon cancer xenografts. Hum. Gene Ther. 10, 1021-1030 (1999).
97. 6-methylguanine-DNA methyltransferase-transduced marrow progenitors repopulate nonmyeloablated mice after drug selection. Blood 95, 3078-3084 (2000). A clear demonstration of the capacity of MGMT resistance systems to protect haematopoietic cells and allow for in vivo stem-cell selection. In this study, selection was used to overcome the requirement for myeloablation before transplant.
98. Ragg, S. et al. Direct reversal of DNA damage by mutant methyltransferase protein protects mice against dose-intensified chemotherapy and leads to in vivo selection of hematopoietic stem cells. Cancer Res. 60, 5187-5195 (2000).
99. + hematopoietic progenitors at low multiplicity of infection confers significant resistance to BG/BCNU and allows selection in vitro. Mol. Ther. 5, 381-387 (2002).
100. Cavazzana-Calvo, M. et al. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 288, 669-672 (2000). Proof that gene therapy directed at stem cells is clinically effective. This study used a corrective gene-therapy vector to treat severe combined immunodeficiency.
101. Malech, H. L. et al. Prolonged production of NADPH oxidase-corrected granulocytes after gene therapy of chronic granulomatous disease. Proc. Natl Acad. Sci. USA 94, 12133-12138 (1997).
102. Persons, D. A. et al. Functional requirements for phenotypic correction of murine β-thalassemia: implications for human gene therapy. Blood 97, 3275-3282 (2001).
103. Hesdorffer, C. et al. Phase I trial of retroviral-mediated transfer of the human MDR1 gene as marrow chemoprotection in patients undergoing high-dose chemotherapy and autologous stem-cell transplantation. J. Clin. Oncol. 16, 165-172 (1998).
104. Hanania, E. G. et al. Results of MDR-1 vector modification trial indicate that granulocyte/macrophage colony-forming unit cells do not contribute to posttransplant hematopoietic recovery following intensive systemic therapy. Proc. Natl Acad. Sci. USA 93, 15346-15351 (1996).
105. Cowan, K. H. et al. Paclitaxel chemotherapy after autologous stem-cell transplantation and engraftment of hematopoietic cells transduced with a retrovirus containing the multidrug resistance complementary DNA (MDR1) in metastatic breast cancer patients. Clin. Cancer Res. 5, 1619-1628 (1999).
106. Moscow, J. A. et al. Engraftment of MDR1 and NeoR gene-transduced hematopoietic cells after breast cancer chemotherapy. Blood 94, 52-61 (1999).
107. Abonour, R. et al. Efficient retrovirus-mediated transfer of the multidrug resistance 1 gene into autologous human long-term repopulating hematopoietic stem cells. Nature Med. 6, 652-658 (2000). A clinical trial of MDR1 gene therapy reporting significant levels of transduced blood cells in the bone marrow of adult cancer patients.
108. Hanenberg, H. et al. Colocalization of retrovirus and target cells on specific fibronectin fragments increases genetic transduction of mammalian cells. Nature Med. 2, 876-882 (1996). The discovery that fibronectin fragments can enhance stem-cell gene transfer. This led to the widespread use of this technique in clinical gene-therapy protocols.
109. Moritz, T. et al. Fibronectin improves transduction of reconstituting hematopoietic stem cells by retroviral vectors: evidence of direct viral binding to chymotryptic carboxy-terminal fragments. Blood 88, 855-862 (1996).
110. Moritz, T., Patel, V. P. & Williams, D. A. Bone marrow extracellular matrix molecules improve gene transfer into human hematopoietic cells via retroviral vectors. J. Clin. Invest. 93, 1451-1457 (1994).