Gene Therapy

  • Jeffrey S. Bartlett
Part of the Pathology and Laboratory Medicine book series (PLM)


Genetic disorders account for a significant amount of human disease. About 4% of all infants born in the United States and Canada are affected by a birth defect. Approximately 1 in 200 births is affected by a chromosomal abnormality, whereas between 1 and 2 in 100 births are affected by a single gene disorder, most often recessive in character. The remainder of the disorders are presumed to be multifactorial in etiology, that is, involve more than one gene or are influenced by external factors. Although most genetic disorders are quite rare, there are several thousand of these disorders that are known, or suspected, to result from single gene defects. Many of these disorders are well known, such as sickle-cell anemia, CF*, muscular dystrophy, β-thalassemia, and PKU. Others are less common, but no less devastating to their victims; for example, the SCID syndromes, Lesh-Nyhan syndrome, and the various lipid and carbohydrate storage diseases.


Gene Therapy Gene Transfer Cationic Lipid Hepatitis Delta Virus Cytosine Deaminase 
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  1. 1.
    Smale, S. T. and Baltimore, D. The “initiator” as a transcriptional control element. Cell 57:103–113, 1989.PubMedCrossRefGoogle Scholar
  2. 2.
    Javahery, R., Khachi, A., Lo, K., Zenzie-Gregory, B., and Smale, S. T. DNA sequence requirements for transcriptional initiator activity in mammalian cells. Mol. Cell. Biol. 14:116–127, 1994.Google Scholar
  3. 3.
    Palmer, T. D., Rosman, G. J., Osborne, W. R. A., and Miller, A. D. Genetically modified skin fibroblasts persist long after transplantation but gradually inactivate introduced genes. Proc. Natl. Acad. Sci. USA 88:4626–4630, 1991.CrossRefGoogle Scholar
  4. 4.
    Scharfmann, R., Axelrod, J. H., and Verma, I. M. Long-term in vivo expression of retrovirus-mediated gene transfer in mouse fibroblast implants. Proc. Natl. Acad. Sci. USA 88:1330–1334, 1991.CrossRefGoogle Scholar
  5. 5.
    Challita, P.-M. and Kohn, D. B. Lack of expression from a retroviral vector after transduction of murine hematopoietic stem cells is associated with methylation in vivo. Proc. Natl. Acad. Sci. USA 91:2567–2571, 1994.PubMedCrossRefGoogle Scholar
  6. 6.
    Kozak, M. An analysis of 5’-noncoding sequences from 699 vertebrate messenger RNAs. Nucleic Acids Res. 15:8125–8148, 1987.PubMedCrossRefGoogle Scholar
  7. 7.
    Jang, S. K., Krausslich, H., Nicklin, M. J. H., Duke, G. M., Palmenberg, A. C., and Wimmer, E. A segment of the 5’ nontranslated region of encephalomyocarditis virus RNA directs internal entry of ribosomes during in vitro translation. J. Virol. 62:2636, 1988.PubMedGoogle Scholar
  8. 8.
    Graham, F. L. and van der Eb, A. A new technique for the assay of infectivity of human adenovirus IV DNA. Virology 102:420, 1973.Google Scholar
  9. 9.
    Wigler, M., Silverstein, S., Lee, L. S., Pellicer, A., Cheng, V. C., and Axel, R. Transfer of purified herpes virus thymidine kinase gene to cultured mouse cells. Cell 11:223, 1977.PubMedCrossRefGoogle Scholar
  10. 10.
    Felgner, P. L., Gadek, T. R., Holm, M., Roman, R., Chan, H. W., Wenz, M., Northrop, J. P., Ringold, G. M., and Danielson, M. Lipofectin: a highly efficient, lipid-mediated DNAtransfection procedure. Proc. Natl. Acad. Sci. USA 84:7413–7417, 1987.PubMedCrossRefGoogle Scholar
  11. 11.
    Felgner, P. L. and Ringold, G. M. Cationic liposome-mediated transfection. Nature 337:387,388, 1989.Google Scholar
  12. 12.
    Felgner, J. H., Kumar, R. , Sridhar, C. N., Wheeler, C. J., Tsai, Y. J., Border, R., Ramsey, P., Martin, M., and Felgner, P. L. Enhanced gene delivery and mechanism studies with a novel series of cationic lipid formulations. J. Biol. Chem. 269:2550–2561, 1994.PubMedGoogle Scholar
  13. 13.
    McLachlan, G., Davidson, H., Davidson, D., Dickenson, P., Dorin, J., and Porteous, D. DOTAP as a vehicle for efficient gene delivery in vitro and in vivo. Biochemica 11: 19–21, 1994.Google Scholar
  14. 14.
    Zhou, X. H., Klibanov, A. L., and Huang, L. Lipophilic polylysines mediate efficient DNA transfection in mammalian cells. Biochim. Biophys. Acta 1065:8–14, 1991PubMedCrossRefGoogle Scholar
  15. 15.
    Zhou, X. and Huang, L. DNA transfection mediated by cationic liposomes containing lipopolylysine: characterization and mechanism of action. Biochim. Biophys. Acta 1189:195–203, 1994.PubMedCrossRefGoogle Scholar
  16. 16.
    Gao, X. A. and Huang, L. A novel cationic liposome reagent for efficient transfection of mammalian cells. Biochem. Biophys. Res. Commun. 179:280–285, 1991.PubMedCrossRefGoogle Scholar
  17. 17.
    Behr, J. P., Demeneix, B., Leoffler, J. P., and Perez-Mutul, J. Efficient gene transfer into mammalian primary endocrine cells with lipopolyamine-coated DNA. Proc. Natl. Acad. Sci. USA 86:6982–6986, 1989.CrossRefGoogle Scholar
  18. 18.
    Barthel, F., Remy, J. S., Leoffler, J. P., and Behr, J. P. Gene transfer optimization with lipospermine-coated DNA. DNA Cell Biol. 12:553–560, 1993.PubMedCrossRefGoogle Scholar
  19. 19.
    Pinnaduwage, P., Schmitt, L., and Huang, L. Use of a quatemary ammonium detergent in liposome mediated DNA transfection of mouse L-cells. Biochim. Biophys. Acta 985:33–37, 1989.PubMedCrossRefGoogle Scholar
  20. 20.
    Wu, G. Y. and Wu, C. H. Receptor-mediated in vitro gene transformation by a soluble DNA carrier system. J. Biol. Chem. 262:4429–4432, 1987.PubMedGoogle Scholar
  21. 21.
    Wu, G. Y. and Wu, C. H. Evidence for targeted gene delivery to HepG2 hepatoma cells in vitro. Biochemistry 27:887–892, 1988.PubMedCrossRefGoogle Scholar
  22. 22.
    Wagner, E., Zenke, M., Cotten, M., Beug, H., and Birnstiel, M. L. Transferrin-polycation conjugates as carriers for DNA uptake into cells. Proc. Natl. Acad. Sci. USA 87:3410–3414, 1990.PubMedCrossRefGoogle Scholar
  23. 23.
    Wagner, E., Cotten, M., Foisner, R., and Birnstiel, M. L. Transferrin-polycation-DNA complexes: the effect of polycations on the structure of the complex and DNA delivery to cells. Proc. Natl. Acad. Sci. USA 88:4255–4259, 1991.PubMedCrossRefGoogle Scholar
  24. 24.
    Blumenthal, R., Seth, P., Willingham, M. C., and Pastan, I. pH-Dependent lysis of liposomes by adenovirus. Biochemistry 25:2231–2237, 1986.PubMedCrossRefGoogle Scholar
  25. 25.
    Rosenfeld, M. A., Yoshimura, K., Trapnell, B. C., Yoneyama, K., Rosenthal, E. R., Dalemans, W., Fukayama, M., Bargon, J., Stier, L. E., Stratford-Perricaudet, L., Perricaudet, M., Guggino, W. B., Pavirani, A., Lecocq, J.-P., and Crystal, R. G. In vivo transfer of the human cystic fibrosis transmembrane conductance regulator gene to the airway epithelium. Cell 68:143–55, 1992.PubMedCrossRefGoogle Scholar
  26. 26.
    Engelhardt, J. F., Simon, R. H., Yang, Y., Zepeda, M., Weber-Pendleton, S., Doranz, B., Grossman, M., and Wilson, J. M. Adenovirus-mediated transfer of the CFTR gene to lung of nonhuman primates: biological efficacy study. Hum. Gene Ther. 4:759–769, 1993.PubMedCrossRefGoogle Scholar
  27. 27.
    Akli, S., Caillaud, C., Vigne, E., Stratford-Perricaudet, L. D., Poenaru, L., Perricaudet, M., Kahn, A., and Peschanski, M. R. Transfer of a foreign gene into the brain using adenovirus vectors. Nature Genet. 3:224–228, 1993.PubMedCrossRefGoogle Scholar
  28. 28.
    Brody, S. L. and Crystal, R. G. Adenovirus-mediated in vivo gene transfer. Ann. NYAcad. Sci. 31:90–101, 1994.CrossRefGoogle Scholar
  29. 29.
    Setoguchi, Y., Jaffe, H. A., Danel, C., and Crystal, R. G. Ex vivo and in vivo gene transfer to the skin using replication-deficient recombinant adenovirus vectors. J. Invest. Dermatol. 102:415–421, 1994.PubMedCrossRefGoogle Scholar
  30. 30.
    Hermonat, P. L. and Muzyczka, N. Use of adeno-associated virus as a mammalian DNA cloning vector: transduction of neomycin resistance into mammalian tissue culture cells. Proc. Natl. Acad. Sci. USA 81:6466–6470, 1984.PubMedCrossRefGoogle Scholar
  31. 31.
    LaFace, D., Hermonat, P. L., Wakeland, E., and Peck, A. Gene transfer into hematopoietic progenitor cells mediated by an adeno-associated virus vector. Virology 162:483–486, 1988.PubMedCrossRefGoogle Scholar
  32. 32.
    Muzyczka, M. Use of adeno-associated virus as a general transduction vector for mammalian cells. Curr. Top. Microbiol. Immunol. 158:97–129, 1992.PubMedCrossRefGoogle Scholar
  33. 33.
    Tratschin, J.-D, West, M. H. P., Sandbank, T., and Carter, B. J. A human parvovirus, adeno-associated virus, as a eukaryotic vector: transient expression and encapsidation of the prokaryotic gene for chloramphenicol acetyltransrerase. Mol. Cell. Biol. 4:2072–2081, 1984.PubMedGoogle Scholar
  34. 34.
    Kumar, S. and Leffak, M. Conserved chromatin structure in c-myc 5’ flanking DNA after viral transduction. J. Mol. Biol. 222:45–57, 1991.PubMedCrossRefGoogle Scholar
  35. 35.
    Walsh, C. E., Liu, J. M., Xiao, X., Young, N. S., Nienhuis, A. W., and Samulski, R. J. Regulated high level expression of a human y-globin gene introduced into erythroid cells by an adeno-associated virus vector. Proc. Natl. Acad. Sci. USA 89:7257–7261, 1992.PubMedCrossRefGoogle Scholar
  36. 36.
    Goodman, S., Xiao, X., Donahue, R. E., Moulton, A., Miller, J., Walsh, C., Young, N. S., Samulski, R. J., and Nienhuis, A. W. Recombinant adeno-associated virus-mediated gene transfer into hematopoietic progenitor cells. Blood 84:1492–1500, 1994.PubMedGoogle Scholar
  37. 37.
    Walsh, C. E., Nienhuis, A. W., Samulski, R. J., Brown, M. G., Miller, J. L., Young, N. S., and Liu, J. M. Phenotypic correction of Fanconi anemia in human hematopoietic cells with a recombinant adeno-associated virus vector. J. Clin. Invest. 94:1440–1448, 1994.PubMedCrossRefGoogle Scholar
  38. 38.
    Nabel, G. J., Chang, A., Nabel, E. G., and Plautz, G. Immunotherapy of malignancy by in vivo gene transfer into tumors. Hum. Gene Ther. 3:399–410, 1992.CrossRefGoogle Scholar
  39. 39.
    Oldfield, E. H., Culver, K. W., and Anderson, W. F. A clinical protocol: gene therapy for the treatment of brain tumors using intratumoral transduction with thymidine kinase gene and intravenous ganciclovir. Hum. Gene Ther. 4:39–69, 1993.PubMedCrossRefGoogle Scholar
  40. 40.
    Gansbacher, B., Houghton, A., and Livingston, P. A pilot study of immunization with HLA-A2 matched allogeneic melanoma cells that secrete interleukin-2 in patients with metastatic melanoma. Hum. Gene Ther. 3:677–690, 1992.CrossRefGoogle Scholar
  41. 41.
    Gansbacher, B., Motzer, R., Houghton, A., and Bander, N. A pilot study of immunization with interleukin-2-secreting allogeneic HLA-A2 matched renal cell carcinoma cells in patients with advanced renal cell carcinoma. Hum. Gene Ther. 3:691–703, 1992.CrossRefGoogle Scholar
  42. 42.
    Rosenberg, S. A. The immunotherapy and gene therapy of cancer. J. Clin. Oncol. 10:180– 199, 1992.PubMedGoogle Scholar
  43. 43.
    Rosenberg, S. A., Anderson, W. F., Asher, A. L., Blaese, M. R., Ettinghausen, S. S., Hwu, P., et al. Immunization of cancer patients using autologous cancer cells modified by insertion of the gene for tumor necrosis factor. Hum. Gene Ther. 3:57–73, 1992.CrossRefGoogle Scholar
  44. 44.
    Rosenberg, S. A., Anderson, W. F., Asher, A. L., Blaese, M. R., Ettinghausen, S. S., Hwu, P., et al. TNF/TIL human gene therapy clinical protocol. Hum. Gene Ther. 1:443–462, 1990.CrossRefGoogle Scholar
  45. 45.
    Rosenberg, S. A., Packard, B. S., Aebersold, P. M., Solomon, D., Topalian, S. L., Toy, S. T., Simon, P., Lotze, M. T., Yang, J. C., Seipp, C. A., Simpson, C., Carter, C., Bock, S., Schwartzentruber, D., Wei, J. P., and White, D. E. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. New Engl. J. Med. 319:1676–1680, 1988.Google Scholar
  46. 46.
    Culver, K. W., Ram, Z., and Walbridge, S. In vivo gene transfer with retroviral vector producer cells for treatment of experimental brain tumors. Science 256:1550–1552, 1992.PubMedCrossRefGoogle Scholar
  47. 47.
    Moolten, F. L. Tumor chemosensitivity conferred by inserted herpes thymidine kinase genes: paradigm for a prospective cancer control strategy. Cancer Res. 46:5276–5281, 1986.PubMedGoogle Scholar
  48. 48.
    Austin, E. A. and Huber, B. E. A first step in the development of gene therapy for colorectal carcinoma: cloning, sequencing, and expression of Escherichia coli cytosine deaminase. Mol. Pharmacol. 43:380–387, 1993.PubMedGoogle Scholar
  49. 49.
    Mroz, P. J. and Moolten, F. L. Retrovirally transduced Escherichia coli gpt genes combine selectability with chemosensitivity capable of mediating tumor eradication. Hum. Gene Ther. 4:589–595, 1993.PubMedCrossRefGoogle Scholar
  50. 50.
    Mullen, C. A., Coale, M. M., Lowe, R., and Blaese, R. M. Tumors expressing the cytosine deaminase suicide gene can be eliminated in vivo with 5-fluorocytosine and induce protective immunity to wild type tumor. Cancer Res. 54:1503–1506, 1994.PubMedGoogle Scholar
  51. 51.
    Mullen, C. A., Kilstrup, M., and Blaese, R. M. Transfer of a bacterial gene for cytosine deaminase to mammalian cells confers lethal sensitivity to 5-fluorocytosine: a negative selection system. Proc. Natl. Acad. Sci. USA 89:33–37, 1992.PubMedCrossRefGoogle Scholar
  52. 52.
    Nabel, G. J., Nabel, E. G., Yang, Z., Fox, B. A., Plautz, G. E., Gao, X., Huang, L., Shu, S., Gordon, D., and Chang, A. E. Direct gene transfer with DNA-liposome complexes in melanoma: expression, biologic activity, and lack of toxicity in humans. Proc. Natl. Acad. Sci. USA 90:11307–11311, 1993.PubMedCrossRefGoogle Scholar
  53. 53.
    Ostrand-Rosenberg, S., Thakur, A., and Clements, V. Rejection of mouse sarcoma cells after transfection of MHC class II genes. J. Immunol. 144:4068–4071, 1990.PubMedGoogle Scholar
  54. 54.
    Fujiwara, T., Grimm, E. A., Cai, D. W., Owen-Schaub, L. B., and Roth, J. A. A retroviral wild-type p53 expression vector penetrates human lung cancer spheroids and inhibits growth by inducing apoptosis. Cancer Res. 53:4129–4133, 1993.PubMedGoogle Scholar
  55. 55.
    Kashani-Sabet, M., Funato, T., Florenes, V. A., Fodstad, 0., and Scanlon, K. J. Suppression of the neoplastic phenotype in vivo by an anti-ras ribozyme. Cancer Res. 54:900–902, 1994.PubMedGoogle Scholar
  56. 56.
    Zhang, Y., Mukhopadhyay, T., Donehower, Georges, R. N., and Roth, J. A. Retroviral vector-mediated transduction of K-ras antisense RNA into human lung cancer cells inhibits expression of the malignant phenotype. Hum. Gene Ther. 4:451–460, 1993.PubMedCrossRefGoogle Scholar
  57. 57.
    McLachlin, J. R., Eglitis, M. A., Ueda, K., Kantoff, P. W., Pastan, I. H., Anderson, W. F., and Gottesman, M. M. Expression of a human complementary DNA for the multidrug resistance gene in murine hematopoietic precursor cells with the use of retroviral gene transfer. J. Natl. Cancer Inst. 82:1260–1263, 1990.PubMedCrossRefGoogle Scholar
  58. 58.
    Sorrentino, B. P., Brandt, S. J., Bodine, D., Gottesman, M., Pastan, I., Cline, A., and Nienhuis, A. W. Selection of drug-resistant bone marrow cells in vivo after retroviral transfer of human MDR-I. Science 257:99–103, 1992.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 1997

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  • Jeffrey S. Bartlett

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