Skip to main content
PMC home page
The Western Journal of Medicine logoLink to The Western Journal of Medicine
. 1994 Sep;161(3):260–263.

Gene therapy for diseases of the nervous system.

J Fick 1, M A Israel 1
PMCID: PMC1011407  PMID: 7975564

Abstract

Advances in molecular biology and recombinant DNA technologies have contributed to our understanding of the molecular basis of many diseases. Now the possibility of gene transfer into normal cells to produce a gene product of therapeutic potential, or into diseased cells to correct the pathologic alteration, promises to revolutionize medical practice. In contemporary medicine, many therapeutic strategies focus on the link between a biochemical deficiency and the ensuing disorder. The treatment of noninfectious disease is often based on replacement therapy; medication is given to compensate for biochemical defects and to prevent or reverse the progression of disease. Although conventional therapies seldom alter the fundamental cause of a disease, gene therapy potentially could correct, at a molecular level, the genetic abnormalities contributing to its pathogenesis. Treatment directed at specific molecular alterations associated with the development of neurologic disease provides expectations of more effective and less toxic therapy. The development of gene therapy for nervous system tumors has progressed rapidly and may be prototypical in the development of therapies for inherited and acquired disorders of the nervous system. We describe possible strategies for using gene therapy to treat nervous system disorders, and we review recent advances in gene therapy for nervous system tumors.

Full text

PDF
260

Images in this article

260Image
on p.260

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akli S., Caillaud C., Vigne E., Stratford-Perricaudet L. D., Poenaru L., Perricaudet M., Kahn A., Peschanski M. R. Transfer of a foreign gene into the brain using adenovirus vectors. Nat Genet. 1993 Mar;3(3):224–228. doi: 10.1038/ng0393-224. [DOI] [PubMed] [Google Scholar]
  2. Anderson W. F. Human gene therapy. Science. 1992 May 8;256(5058):808–813. doi: 10.1126/science.1589762. [DOI] [PubMed] [Google Scholar]
  3. Bajocchi G., Feldman S. H., Crystal R. G., Mastrangeli A. Direct in vivo gene transfer to ependymal cells in the central nervous system using recombinant adenovirus vectors. Nat Genet. 1993 Mar;3(3):229–234. doi: 10.1038/ng0393-229. [DOI] [PubMed] [Google Scholar]
  4. Barba D., Hardin J., Ray J., Gage F. H. Thymidine kinase-mediated killing of rat brain tumors. J Neurosurg. 1993 Nov;79(5):729–735. doi: 10.3171/jns.1993.79.5.0729. [DOI] [PubMed] [Google Scholar]
  5. Bi W. L., Parysek L. M., Warnick R., Stambrook P. J. In vitro evidence that metabolic cooperation is responsible for the bystander effect observed with HSV tk retroviral gene therapy. Hum Gene Ther. 1993 Dec;4(6):725–731. doi: 10.1089/hum.1993.4.6-725. [DOI] [PubMed] [Google Scholar]
  6. Blaese R. M., Culver K. W., Chang L., Anderson W. F., Mullen C., Nienhuis A., Carter C., Dunbar C., Leitman S., Berger M. Treatment of severe combined immunodeficiency disease (SCID) due to adenosine deaminase deficiency with CD34+ selected autologous peripheral blood cells transduced with a human ADA gene. Amendment to clinical research project, Project 90-C-195, January 10, 1992. Hum Gene Ther. 1993 Aug;4(4):521–527. doi: 10.1089/hum.1993.4.4-521. [DOI] [PubMed] [Google Scholar]
  7. Blaese R. M., Culver K. W. Gene therapy for primary immunodeficiency disease. Immunodefic Rev. 1992;3(4):329–349. [PubMed] [Google Scholar]
  8. Breakefield X. O. Gene delivery into the brain using virus vectors. Nat Genet. 1993 Mar;3(3):187–189. doi: 10.1038/ng0393-187. [DOI] [PubMed] [Google Scholar]
  9. Brenner M. K., Rill D. R., Moen R. C., Krance R. A., Mirro J., Jr, Anderson W. F., Ihle J. N. Gene-marking to trace origin of relapse after autologous bone-marrow transplantation. Lancet. 1993 Jan 9;341(8837):85–86. doi: 10.1016/0140-6736(93)92560-g. [DOI] [PubMed] [Google Scholar]
  10. Caruso M., Panis Y., Gagandeep S., Houssin D., Salzmann J. L., Klatzmann D. Regression of established macroscopic liver metastases after in situ transduction of a suicide gene. Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):7024–7028. doi: 10.1073/pnas.90.15.7024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Chiocca E. A., Choi B. B., Cai W. Z., DeLuca N. A., Schaffer P. A., DiFiglia M., Breakefield X. O., Martuza R. L. Transfer and expression of the lacZ gene in rat brain neurons mediated by herpes simplex virus mutants. New Biol. 1990 Aug;2(8):739–746. [PubMed] [Google Scholar]
  12. Culver K. W., Anderson W. F., Blaese R. M. Lymphocyte gene therapy. Hum Gene Ther. 1991 Summer;2(2):107–109. doi: 10.1089/hum.1991.2.2-107. [DOI] [PubMed] [Google Scholar]
  13. Culver K. W., Ram Z., Wallbridge S., Ishii H., Oldfield E. H., Blaese R. M. In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. Science. 1992 Jun 12;256(5063):1550–1552. doi: 10.1126/science.1317968. [DOI] [PubMed] [Google Scholar]
  14. Culver K., Cornetta K., Morgan R., Morecki S., Aebersold P., Kasid A., Lotze M., Rosenberg S. A., Anderson W. F., Blaese R. M. Lymphocytes as cellular vehicles for gene therapy in mouse and man. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3155–3159. doi: 10.1073/pnas.88.8.3155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Davidson B. L., Allen E. D., Kozarsky K. F., Wilson J. M., Roessler B. J. A model system for in vivo gene transfer into the central nervous system using an adenoviral vector. Nat Genet. 1993 Mar;3(3):219–223. doi: 10.1038/ng0393-219. [DOI] [PubMed] [Google Scholar]
  16. Ezzeddine Z. D., Martuza R. L., Platika D., Short M. P., Malick A., Choi B., Breakefield X. O. Selective killing of glioma cells in culture and in vivo by retrovirus transfer of the herpes simplex virus thymidine kinase gene. New Biol. 1991 Jun;3(6):608–614. [PubMed] [Google Scholar]
  17. Freeman S. M., Abboud C. N., Whartenby K. A., Packman C. H., Koeplin D. S., Moolten F. L., Abraham G. N. The "bystander effect": tumor regression when a fraction of the tumor mass is genetically modified. Cancer Res. 1993 Nov 1;53(21):5274–5283. [PubMed] [Google Scholar]
  18. Friedmann T. Progress toward human gene therapy. Science. 1989 Jun 16;244(4910):1275–1281. doi: 10.1126/science.2660259. [DOI] [PubMed] [Google Scholar]
  19. Gage F. H., Kawaja M. D., Fisher L. J. Genetically modified cells: applications for intracerebral grafting. Trends Neurosci. 1991 Aug;14(8):328–333. doi: 10.1016/0166-2236(91)90156-o. [DOI] [PubMed] [Google Scholar]
  20. Gage F. H., Wolff J. A., Rosenberg M. B., Xu L., Yee J. K., Shults C., Friedmann T. Grafting genetically modified cells to the brain: possibilities for the future. Neuroscience. 1987 Dec;23(3):795–807. doi: 10.1016/0306-4522(87)90159-x. [DOI] [PubMed] [Google Scholar]
  21. Jiao S., Gurevich V., Wolff J. A. Long-term correction of rat model of Parkinson's disease by gene therapy. Nature. 1993 Apr 1;362(6419):450–453. doi: 10.1038/362450a0. [DOI] [PubMed] [Google Scholar]
  22. Karp J. E., Broder S. New directions in molecular medicine. Cancer Res. 1994 Feb 1;54(3):653–665. [PubMed] [Google Scholar]
  23. Mahaley M. S., Jr, Mettlin C., Natarajan N., Laws E. R., Jr, Peace B. B. National survey of patterns of care for brain-tumor patients. J Neurosurg. 1989 Dec;71(6):826–836. doi: 10.3171/jns.1989.71.6.0826. [DOI] [PubMed] [Google Scholar]
  24. Miller A. D. Human gene therapy comes of age. Nature. 1992 Jun 11;357(6378):455–460. doi: 10.1038/357455a0. [DOI] [PubMed] [Google Scholar]
  25. 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. 1990 Aug;10(8):4239–4242. doi: 10.1128/mcb.10.8.4239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Moolten F. L. Tumor chemosensitivity conferred by inserted herpes thymidine kinase genes: paradigm for a prospective cancer control strategy. Cancer Res. 1986 Oct;46(10):5276–5281. [PubMed] [Google Scholar]
  27. Moolten F. L., Wells J. M. Curability of tumors bearing herpes thymidine kinase genes transferred by retroviral vectors. J Natl Cancer Inst. 1990 Feb 21;82(4):297–300. doi: 10.1093/jnci/82.4.297. [DOI] [PubMed] [Google Scholar]
  28. Mulligan R. C. The basic science of gene therapy. Science. 1993 May 14;260(5110):926–932. doi: 10.1126/science.8493530. [DOI] [PubMed] [Google Scholar]
  29. Oldfield E. H., Ram Z., Culver K. W., Blaese R. M., DeVroom H. L., Anderson W. F. Gene therapy for the treatment of brain tumors using intra-tumoral transduction with the thymidine kinase gene and intravenous ganciclovir. Hum Gene Ther. 1993 Feb;4(1):39–69. doi: 10.1089/hum.1993.4.1-39. [DOI] [PubMed] [Google Scholar]
  30. Olson L. NGF and the treatment of Alzheimer's disease. Exp Neurol. 1993 Nov;124(1):5–15. doi: 10.1006/exnr.1993.1167. [DOI] [PubMed] [Google Scholar]
  31. Ram Z., Culver K. W., Walbridge S., Blaese R. M., Oldfield E. H. In situ retroviral-mediated gene transfer for the treatment of brain tumors in rats. Cancer Res. 1993 Jan 1;53(1):83–88. [PubMed] [Google Scholar]
  32. Ram Z., Culver K. W., Walbridge S., Frank J. A., Blaese R. M., Oldfield E. H. Toxicity studies of retroviral-mediated gene transfer for the treatment of brain tumors. J Neurosurg. 1993 Sep;79(3):400–407. doi: 10.3171/jns.1993.79.3.0400. [DOI] [PubMed] [Google Scholar]
  33. Roe T., Reynolds T. C., Yu G., Brown P. O. Integration of murine leukemia virus DNA depends on mitosis. EMBO J. 1993 May;12(5):2099–2108. doi: 10.1002/j.1460-2075.1993.tb05858.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Rosenberg M. B., Friedmann T., Robertson R. C., Tuszynski M., Wolff J. A., Breakefield X. O., Gage F. H. Grafting genetically modified cells to the damaged brain: restorative effects of NGF expression. Science. 1988 Dec 16;242(4885):1575–1578. doi: 10.1126/science.3201248. [DOI] [PubMed] [Google Scholar]
  35. Rosenberg S. A., Aebersold P., Cornetta K., Kasid A., Morgan R. A., Moen R., Karson E. M., Lotze M. T., Yang J. C., Topalian S. L. Gene transfer into humans--immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction. N Engl J Med. 1990 Aug 30;323(9):570–578. doi: 10.1056/NEJM199008303230904. [DOI] [PubMed] [Google Scholar]
  36. Rosenberg S. A., Anderson W. F., Blaese M., Hwu P., Yannelli J. R., Yang J. C., Topalian S. L., Schwartzentruber D. J., Weber J. S., Ettinghausen S. E. The development of gene therapy for the treatment of cancer. Ann Surg. 1993 Oct;218(4):455–464. doi: 10.1097/00000658-199310000-00006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Short M. P., Choi B. C., Lee J. K., Malick A., Breakefield X. O., Martuza R. L. Gene delivery to glioma cells in rat brain by grafting of a retrovirus packaging cell line. J Neurosci Res. 1990 Nov;27(3):427–439. doi: 10.1002/jnr.490270322. [DOI] [PubMed] [Google Scholar]
  38. Sikora K. Gene therapy for cancer. Eur J Cancer. 1991;27(9):1069–1070. doi: 10.1016/0277-5379(91)90292-l. [DOI] [PubMed] [Google Scholar]
  39. Springett G. M., Moen R. C., Anderson S., Blaese R. M., Anderson W. F. Infection efficiency of T lymphocytes with amphotropic retroviral vectors is cell cycle dependent. J Virol. 1989 Sep;63(9):3865–3869. doi: 10.1128/jvi.63.9.3865-3869.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Takamiya Y., Short M. P., Ezzeddine Z. D., Moolten F. L., Breakefield X. O., Martuza R. L. Gene therapy of malignant brain tumors: a rat glioma line bearing the herpes simplex virus type 1-thymidine kinase gene and wild type retrovirus kills other tumor cells. J Neurosci Res. 1992 Nov;33(3):493–503. doi: 10.1002/jnr.490330316. [DOI] [PubMed] [Google Scholar]
  41. Takamiya Y., Short M. P., Moolten F. L., Fleet C., Mineta T., Breakefield X. O., Martuza R. L. An experimental model of retrovirus gene therapy for malignant brain tumors. J Neurosurg. 1993 Jul;79(1):104–110. doi: 10.3171/jns.1993.79.1.0104. [DOI] [PubMed] [Google Scholar]
  42. Thompson L. At age 2, gene therapy enters a growth phase. Science. 1992 Oct 30;258(5083):744–746. doi: 10.1126/science.1472258. [DOI] [PubMed] [Google Scholar]
  43. Vile R. G., Hart I. R. Use of tissue-specific expression of the herpes simplex virus thymidine kinase gene to inhibit growth of established murine melanomas following direct intratumoral injection of DNA. Cancer Res. 1993 Sep 1;53(17):3860–3864. [PubMed] [Google Scholar]

Articles from Western Journal of Medicine are provided here courtesy of BMJ Publishing Group

RESOURCES