Share This Article:

Gene therapy strategies for treating brain tumors: Retroviruses are still good candidates for therapeutic vectors

Abstract Full-Text HTML XML Download Download as PDF (Size:697KB) PP. 12-18
DOI: 10.4236/ojgen.2013.32A1002    4,211 Downloads   6,367 Views  

ABSTRACT

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults. In the past few decades, many efforts have been made to improve the prognosis of GBM, however, with limited success. Many gene therapy strategies for GBM have been developed and a few have progressed to clinical trials. Retroviral vectors have superior features for gene therapy in brain cancers, including tumor specificity, immunogenicity, and longer half-life. Early gene therapy trials in GBM patients based on transplantation of retrovirus-producing cells into the brain failed to prove efficacious. Adenoviral vectors, which can be prepared as high-titer virus solutions and undergo efficient transduction in tumor cells, failed in clinical trials, likely due to immunogenicity and instability of gene expression. Alternative therapeutics such as oncolytic viruses that specifically target and destroy cancer cells are currently under investigation. In addition to novel vectors, retroviral vectors are still attractive candidates for use in gene therapy against brain tumors. Since yields of properly-packaged viral particles from virus-producing cells have been very limited so far, gene therapy by direct injection of hightiter retroviral vectors into the patients’ brains was not possible. To overcome these disadvantages, a packaging cell line that yields high-titer retroviral solutions was established by our group, enabling the direct injection of massive retroviral vector stocks directly into the brain. Mouse glioma models were effectively cured with a combination of a suicide gene/ prodrug system and a highly-concentrated retrovirus solution. Preclinical assessments, including that of replication-competent retroviruses and tumorigenicity of the combination method, have confirmed the safety of the highly-concentrated retrovirus solution. Addi tional studies are needed to address the clinical utility of such combination gene therapies. Taken together, these data suggest that retroviral vectors are still good candidates for development in gene therapy applications.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Yawata, T. and Shimizu, K. (2013) Gene therapy strategies for treating brain tumors: Retroviruses are still good candidates for therapeutic vectors. Open Journal of Genetics, 3, 12-18. doi: 10.4236/ojgen.2013.32A1002.

References

[1] [1] DeAngelis, L.M., Gutin, P.H., Leibel, S.A. and Posner, J.B. (2002) Intracranial tumors: Diagnosis and treatment. Martin Dunitz, London, 367-394.
[2] Mahaley Jr., M.S., Mettlin, C., Natarajan, N., Laws Jr., E.R. and Peace, B.B. (1989) National survey of patterns of care for brain-tumo patients. Journal of Neurosurgery, 71, 826-836. doi:10.3171/jns.1989.71.6.0826
[3] Deen, D.F., Chiarodo, A., Grimm, E.A., Fike, J.R., Israel, M.A., Kun, L.E., Levin, V.A., Marton, L.J., Packer, R.J., Pegg, A.E., Rosenblum, M.L., Suit, H.D., Walker, M.D., Wikstrand, C.J., Wilson, C.B., Wong, A.J. and Yung, W.K. (1993) Brain tumor working group report on the 9th international conference on brain tumor research and therapy. Organ system program, National Cancer Institute. Journal of Neurosurgery, 16, 243-272. doi:10.1007/BF01057041
[4] Stupp, R., Hegi, M.E., Gilbert, M.R. and Chakravarti, A. (2007) Chemoradiotherapy in malignant glioma: Standard of care and future directions. Journal of Clinical Oncology, 25, 4127-4136. doi:10.1200/JCO.2007.11.8554
[5] Blaese, R.M., Culver, K.W., Miller, A.D., Carter, C.S., Fleisher, T., Clerici, M., Shearer, G., Chang, L., Chiang, Y., Tolstoshev, P., Greenblatt, J.J., Rosenberg, S.A., Klein, H., Berger, M., Mullen, C.A., Ramsey, W.J., Muul, L., Morgan, R.A. and Anderson, W.F. (1995) T lymphocyte-directed gene therapy for ADA-SCID: Initial trial results after 4 years. Science, 270, 475-480. doi:10.1126/science.270.5235.475
[6] Rainov, N.G. and Ren, H. (2003) Clinical trials with retrovirus mediated gene therapy—What have we learned? Journal of Neurooncology, 65, 227-236. doi:10.1023/B:NEON.0000003652.71665.f2
[7] Duarte, S., Carle, G., Faneca, H., de Lima, M.C. and Pierrefite-Carle, V. (2012) Suicide gene therapy in cancer: Where do we stand now? Cancer Letters, 324, 160-170. doi:10.1016/j.canlet.2012.05.023
[8] Bi, W.L., Parysek, L.M., Warnick, R. and Stambrook, P.J. (1993) In vivo evidence that metabolic cooperation is responsible for the bystander effect observed with HSVtk retroviral gene therapy. Human Gene Therapy, 4, 725-731. doi:10.1089/hum.1993.4.6-725
[9] Culver, K.W., Ram, Z., Walbridge, S., Ishii, H., Oldfield, E.H. and Blaese, R.M. (1992) In vivo gene transfer with retroviral vector producer cells for treatment of experimental brain tumors. Science, 256, 1550-1552. doi:10.1126/science.1317968
[10] Yamada, M., Shimizu, K., Miyao, Y., Hayakawa, T., Ikenaka, K., Nakahira, K., Nakajima, K., Kagawa, T. and Mikoshiba, K. (1992) Retrovirus-mediated gene transfer targeted to malignant glioma cells in murine brain. Japan Journal of Cancer Research, 83, 1244-1247. doi:10.1111/j.1349-7006.1992.tb02752.x
[11] Tamura, K., Tamura, M., Ikenaka, K., Yoshimatsu, T., Miyao, Y., Nanmoku, K. and Shimizu, K. (2001) Eradication of murine brain tumors by direct inoculation of concentrated high titer-recombinant retrovirus harboring the herpes simplex virus thymidine kinase gene. Gene Therapy, 8, 215-222. doi:10.1038/sj.gt.3301371
[12] Ram, Z., Culver, K.W., Oshiro, E.M., Viola, J.J., DeVroom, H.L., Otto, E., Long, Z., Chiang, Y., McGarrity, G.J., Muul, L.M., Katz, D., Blaese, R.M. and Oldfield, E.H. (1997) Therapy of malignant brain tumors by intratumoral implantation of retroviral vector-producing cells. Nature Medicine, 3, 1354-1361. doi:10.1038/nm1297-1354
[13] Vincent, A.J., Vogels, R., Someren, V.G., Esandi, M.C., Noteboom, J.L., Avezaat, C.J., Vecht, C., Bekkum, D.W., Valerio, D., Bout, A. and Hoogerbrugge, P.M. (1996) Herpes simplex virus thymidine kinase gene therapy for rat malignant brain tumors. Human Gene Therapy, 7, 197-205. doi:10.1089/hum.1996.7.2-197
[14] Okada, H., Miyamura, K., Itoh, T., Hagiwara, M., Wakabayashi, T., Mizuno, M., Colosi, P., Kurtzman, G. and Yoshida, J. (1996) Gene therapy against an experimental glioma using adeno-associated virus vectors. Gene Therapy, 3, 957-964.
[15] Kramm, C.M., Chase, M., Herrlinger, U., Jacobs, A., Pechan, P.A., Rainov N.G., Sena-Esteves, M., Aghi, M., Barnett, F.H., Chiocca, E.A. and Breakefield, X.O. (1997) Therapeutic efficiency and safety of a second-generation replication-conditional HSV1 vector for brain tumor gene therapy. Human Gene Therapy, 8, 2057-2068. doi:10.1089/hum.1997.8.17-2057
[16] Gene Therapy Clinical Trials Worldwide (2013) Vectors used in gene therapy clinical trails. http://www.abedia.com/wiley/vectors.php
[17] Puumalainen, A., Vapalahti, M., Agrawal, R.S., Kossila, M., Laukkanen, J., Lehtolainen, P., Viita, H., Paljarvi, L., Vanninen, R. and Yla-Herttuala, S. (1998) Beta-galactosidase gene transfer to human malignant glioma in vivo using replication-deficient retroviruses and adenoviruses. Human Gene Therapy, 9, 1769-1774. doi:10.1089/hum.1998.9.12-1769
[18] Sandmair, A.M., Loimas, S., Puranen, P., Immonen, A., Kossila, M., Puranen, M., Hurskainen, H., Tyynela, K., Turunen, M., Vanninen, R., Lehtolainen, P., Paljarvi, L., Johansson, R., Vapalahti, M. and Yla-Herttuala, S. (2000) Thymidine kinase gene therapy for human malignant glioma, using replication-deficient retroviruses or adenoviruses. Human Gene Therapy, 11, 2197-2205. doi:10.1089/104303400750035726
[19] Trask, T.W., Trask, R.P., Aguilar-Cordova, E., Shine, H.D., Wyde, P.R., Goodman, J.C., Hamilton, W.J., Rojas-Martinez, A., Chen, S.H., Woo, S.L. and Grossman, R.G. (2000) Phase I study of adenoviral delivery of the HSV-tk gene and ganciclovir administration in patients with current malignant brain tumors. Molecular Therapy, 1, 195-203. doi:10.1006/mthe.2000.0030
[20] Eck, S.L., Alavi, J.B., Alavi, A., Davis, A., Hackney, D., Judy, K., Mollman, J., Phillips, P.C., Wheeldon, E.B. and Wilson, J.M. (1996) Treatment of advanced CNS malignnancies with the recombinant adenovirus H5.010RSVTK: A phase I trial. Human Gene Therapy, 7, 1465-1482. doi:10.1089/hum.1996.7.12-1465
[21] Germano, I.M., Fable, J., Gultekin, S.H. and Silvers, A. (2003) Adenovirus/herpes simplex-thymidine kinase/ganciclovir complex: Preliminary results of a phase I trial in patients with recurrent glioma. Journal of Neurooncology, 65, 279-289. doi:10.1023/B:NEON.0000003657.95085.56
[22] Smitt, P.S., Driesse, M., Wolbers, J., Kros, M. and Avezaat, C. (2003) Treatment of relapsed malignant glioma with an adenoviral vector containing the herpes simplex thymidine kinase gene followed by ganciclovir. Molecular Therapy, 7, 851-858. doi:10.1016/S1525-0016(03)00100-X
[23] Mitchell, P. (2010) Ark’s gene therapy stumbles at the finish line. Nature Biotechnology, 28, 183-184. doi:10.1038/nbt0310-183
[24] Wollmann, G., Ozduman, K. and van den Pol, A.N. (2012) Oncolytic virus therapy for glioblastoma multiforme: Concepts and candidates. Cancer Journal, 18, 69-81. doi:10.1097/PPO.0b013e31824671c9
[25] De Siva, N., Atkins, H, Kirn, D.H., Bell, J.C. and Breitbach, C.J. (2010) Double trouble for tumors: Exploiting the tumour microenvironment to enhance anticancer effect of oncolytic viruses. Cytokine Growth Factor Review, 21, 135-141. doi:10.1016/j.cytogfr.2010.02.007
[26] Melcher, A., Parato, K., Rooney, C.M. and Bell, J.C. (2011) Thunder and lightning: Immunotherapy and oncolytic viruses collide. Molecular Therapy, 11, 13-21.
[27] Welsh Jr., R.M., Cooper, N.R., Jensen, F.C. and Oldstone, M.B. (1975) Human aserum lyses RNA tumour viruses. Nature, 257, 612-614. doi:10.1038/257612a0
[28] Shimizu, K., Miyao, Y., Tamura, M., Kishima, H., Ohkawa, M., Mabuchi, E., Yamada, M., Hayakawa, T. and Ikenaka, K. (1995) Infectious retrovirus is inactivated by serum but not by cerebrospinal fluid or fluid from tumor bed in patients with malignant glioma. Japan Journal of Cancer Research, 86, 1010-1012. doi:10.1111/j.1349-7006.1995.tb03013.x
[29] Yoshimatsu, T., Tamura, M., Kuriyama, S. and Ikenaka, K. (1998) Improvement of retroviral packaging cell lines by introducing the polyomavirus early region. Human Gene Therapy, 9, 161-172. doi:10.1089/hum.1998.9.2-161
[30] Hacein-Bey-Abina, S.F., Le Deist, F., Carlier, F., Bouneaud, C., Hue, C., De Villartay, J., Thrasher, A.J., Wulffraat, N., Sorensen, R., Dupuis-Girod, S., Fischer, A., Davis, G., Kuis, W., Leiva, L. and Cavazzana-Calvo, M. (2002) Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. New England Journal of Medicine, 346, 1185-1193. doi:10.1056/NEJMoa012616
[31] Hacein-Bey-Abina, S.C., von Kalle, M., Schmidt, M.P., McCormack, M.P., Wulffraat, N., Leboulch, P., Lim, A., Osborne, C.S., Pawliuk, R., Morillon, E., Sorensen, R., Foster, A., Fraser, P., Cohen, J.I., de Saint Basile, G., Alexander, I., Wintergerst, U., Frebourg, T., Aurias, A., Stoppa-Lyonnet, D., Romana, S., Radford-Weiss, I., Gross, F., Valensi, F., Delabesse, E., Macintyre, E., Sigaux, F., Soulier, J., Leiva, L.E., Wissler, M., Prinz, C., Rabbitts, T.H., Le Deist, F., Fischer, A. and Cavazzana-Calvo, M. (2003) LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science, 302, 415-419. doi:10.1126/science.1088547
[32] Miyao, Y., Shimizu, K., Tamura, M., Akita, H., Ikeda, K., Mabuchi, E., Kishima, H., Hayakawa, T. and Ikenaka, K. (1997) Usefulness of a mouse myelin basic protein promoter for gene therapy of malignant glioma: Myelin basic protein is strongly active in human malignant glioma cells. Japan Journal of Cancer Research, 88, 678-686. doi:10.1111/j.1349-7006.1997.tb00436.x
[33] Shinoura, N., Koike, H., Furitu, T., Hashimoto, M., Asai, A., Kirino, T. and Hamada H. (2000) Adenovirus-mediated transfer of caspase-8 augments cell death in gliomas: Implication for gene therapy. Human Gene Therapy, 11, 1123-1137. doi:10.1089/10430340050015185
[34] Shinoura, N., Saito, K., Yoshida, Y., Hashimoto, M., Asai, A., Kirino, T. and Hamada, H. (2000) Adenovirus-mediated transfer of bax with caspase-8 controlled by myelin basic protein promoter exerts an enhanced cytotoxic effect in gliomas. Cancer Gene Therapy, 7, 739-748. doi:10.1038/sj.cgt.7700158
[35] Komata, T., Kondo, Y., Kanzawa, T., Ito, H., Hirohata, S., Koga, S., Sumiyoshi, H., Takakura, M., Inoue, M., Barna, B.P., Germano, I.M., Kyo, S. and Kondo, S. (2002) Caspase-8 gene therapy using the human telomerase reverse transcriptase promoter for malignant glioma cells. Human Gene Therapy, 13, 1015-1025. doi:10.1089/104303402753812421
[36] Yawata, T., Maeda, Y., Okiku, M., Ishida, E., Ikenaka, K. and Shimizu, K. (2011) Identification and functional characterization of glioma-specific promoters and their application in suicide gene therapy. Journal of Neurooncology, 104, 497-507. doi:10.1007/s11060-010-0522-0

  
comments powered by Disqus

Copyright © 2019 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.