Regulatory Aspects in the Development of Gene Therapies

  • Rosemarie Aurigemma
  • Joseph E. Tomaszewski
  • Sheryl Ruppel
  • Stephen Creekmore
  • Edward A. Sausville
Part of the Contemporary Cancer Research book series (CCR)


Preclinical therapeutics development research is directed toward fulfilling two overlapping sets of goals. A set of scientific goals includes defining the best molecule or biologic construct for the task at hand, and proving the case for its development. The second set of goals addresses regulatory requirements necessary to introduce the agent into human subjects. In the case of “small molecule” drugs, in most cases the identity of the molecule and appropriate safety studies are straightforward. In contrast, the development of biologic agents, including gene therapies discussed here, presents distinct challenges. The nature of the “drug” may be an organism subject to mutation or selection of variants through recombination. Its properties may vary depending on the scale and method of its preparation, purification, and storage. How to test adequately for its safety prior to first introduction in humans may not be straightforward owing to intrinsic differences in response to the agent expected in humans as compared to animals.


Adenoviral Vector Severe Combine Immunodeficiency Disease Bovine Immunodeficiency Virus Aotus Monkey Gene Therapy Product 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    ICH guidance on quality of biotechnology/biological products: derivation and characterization of cell substrates used for production of biotechnical/biological products, September 21, 1998. Available on-line at:
  2. 2.
    ICH: final guideline on quality of biotechnological products: analysis of the expression construct in cells used for production of r-DNA derived protein products, February 1996. Available on-line at:
  3. 3.
    ICH guidance on specifications: test procedures and acceptance criteria for biotechnological/biological products, August 18, 1999. Available on-line at:
  4. 4.
    ICH Guidance for Industry Q1A (R2), stability testing of new drug substances and products, November 20, 2003. Available on-line at:
  5. 5.
    ICH guidance on viral safety evaluation of biotechnology products derived from cell lines of human or animal origin, September 24, 1998. Available on-line at:
  6. 6.
    ICH guidance: Q7A good manufacturing practice guidance for active pharmaceutical ingredients, September 25, 2001. Available on-line at:
  7. 7.
    ICH guidance for industry: S6 preclinical safety evaluation of biotechnology-derived pharmaceuticals, July16, 1997. Available on-line at:
  8. 8.
    ICH: final guidance on stability testing of biotechnological/biological products, July 10, 1996. Available on-line at:
  9. 9.
    FDA guidance for industry: guidance for human somatic cell therapy and gene therapy, March 30, 1998. Available on-line at:
  10. 10.
    Check, E. (2002) Gene therapy: a tragic setback. Nature 420, 116–118.PubMedCrossRefGoogle Scholar
  11. 10a.
    FDA Draft Points to Consider in Human Somatic Cell Therapy and Gene Therapy, August 27, 1991.Google Scholar
  12. 11.
    Hacein-Bey-Abina, S., von Kalle, C., Schmidt, M., et al. (2003) A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N. Engl. J. Med. 347, 255–256.CrossRefGoogle Scholar
  13. 12.
    Check, E. (2002) Regulators split on gene therapy as patient shows signs of cancer. Nature 419, 545–546.PubMedCrossRefGoogle Scholar
  14. 13.
    Check, E. (2003) Second cancer case halts gene-therapy trials. Nature 421, 305.PubMedCrossRefGoogle Scholar
  15. 14.
    Pilaro, A. M. and Serabian, M. A. (1999) Preclinical development strategies for novel gene therapy products. Toxicol. Pathol. 27, 4–7.PubMedGoogle Scholar
  16. 15.
    Pilling, A. M. (1999) The role of the toxicologic pathologist in the preclinical safety evaluation of biotechnology-derived pharmaceuticals. Toxicol. Pathol. 27, 678–688.PubMedGoogle Scholar
  17. 16.
    Dempster, A. M. (2000) Nonclinical safety evaluation of biotechnologically derived pharmaceuticals. Biotech. Annu. Rev. 5, 221–258.CrossRefGoogle Scholar
  18. 17.
    Griffiths, S. A. and Lumley, C. E. (1998) Non-clinical safety studies for biotechnology-derived pharmaceuticals: conclusions from an international workshop. Hum. Exp. Toxicol. 17, 63–83.PubMedCrossRefGoogle Scholar
  19. 18.
    ICH guidance to industry: S7A safety pharmacology studies for human pharmaceuticals, July 12, 2001. Available at:
  20. 19.
    Code of Federal Regulations, Title 21, Food and Drugs, Part 610.10, Subpart B, General biological products standards; general provisions; potency, p. 61, revised as of April 1, 2002.Google Scholar
  21. 20.
    Code of Federal Regulations, Title 21, Food and Drugs, Part 610.12, Subpart B, General biological products standards;general provisions; sterility, pp. 63–67, revised as of April 1, 2002.Google Scholar
  22. 21.
    Code of Federal Regulations, Title 21, Food and Drugs, Part 610.13, Subpart B, General biological products standards; general provisions; purity, pp. 67–68, revised as of April 1, 2002.Google Scholar
  23. 22.
    Code of Federal Regulations, Title 21, Food and Drugs, Part 610.14, Subpart B, General biological products standards; general provisions; identity, pp. 68–69, revised as of April 1, 2002.Google Scholar
  24. 23.
    Code of Federal Regulations, Title 21, Food and Drugs, Part 58, Good laboratory practice for nonclinical laboratory studies, pp. 302–316, revised as of April 1, 2002.Google Scholar
  25. 24.
    Code of Federal Regulations, Title 21, Food and Drugs, Part 210, Current good manufacturing practice in manufacturing, processing, packing, or holding of drugs; general, pp. 113–115, revised as of April 1, 2002.Google Scholar
  26. 25.
    Code of Federal Regulations, Title 21, Food and Drugs, Part 211, Current good manufacturing practice for finished pharmaceuticals, pp. 115–135, revised as of April 1, 2002.Google Scholar
  27. 26.
    Code of Federal Regulations, Title 21, Food and Drugs, Part 312, Investigational new drug application, pp. 57–95, revised as of April 1, 2002.Google Scholar
  28. 27.
    FDA guidance for industry: content and format of Investigational New Drug Applications (INDs) for phase I studies of drugs, including well-characterized, therapeutic, biotechnology-derived products, November 1995. Available online at:
  29. 28.
    FDA guidance for industry: IND’s for phases 2 and 3 studies of drugs, including specified therapeutic biotechnology-derived products, chemistry, manufacturing and controls content and format, April 20, 1999. Available on-line at:
  30. 29.
    FDA guidance for industry: content and format of chemistry, manufacturing, and controls information and establishment description information for a vaccine or related product, January 5, 1999. Available on-line at:
  31. 30.
    FDA guidance for industry for the submission of chemistry, manufacturing, and controls information for a therapeutic recombinant DNA-derived product or a monoclonal antibody product for in vivo use, August 1996. Available online at
  32. 31.
    FDA guidance for industry: formal meetings with sponsors and applicants for PDUFA products, March 7, 2000. Available on-line at:
  33. 32.
    FDA points to consider in the manufacturing and testing of monoclonal antibody products for human use, February 28, 1997. Available on-line at:
  34. 33.
    FDA letter to manufacturers of biological products: recommendations regarding bovine spongiform encephalopathy (BSE), April 19, 2000. Available on-line at:
  35. 34.
    FDA Biological Response Modifiers Advisory Committee: current policy on sequence characterization of gene transfer products, November 16, 2000. Available on-line at:
  36. 35.
    FDA Biological Response Modifiers Advisory Committee: adenovirus titer measurements and RCA levels, July 13, 2001. Available on-line at:
  37. 36.
    FDA guidance for industry: supplemental guidance on testing for replication competent retrovirus in retroviral vector based gene therapy products and during follow-up of patients in clinical trials using retroviral vectors, October 18, 2000. Available on-line at:
  38. 37.
    FDA points to consider in the characterization of cell lines used to produce biologicals, May 17, 1993. Available online at:
  39. 38.
    FDA Dear Gene Therapy IND or Master File Sponsor Letter, March 6, 2000. Available on-line at:
  40. 39.
    FDA gene therapy patient tracking system final document, June 27, 2002. Available on-line at:
  41. 40.
    FDA guidance concerning demonstration of comparability of human biological products, including therapeutic biotechnology-derived products, April 1996. Available on-line at:
  42. 41.
    Third national NIH gene transfer safety symposium: safety considerations in the use of AAV vectors in gene transfer clinical trials, March 7, 2001. Available on-line at: 3-7-011.pdf.
  43. 42.
    Cornetta, K. G. and Robertson, M. J. (2000) Basic principles of gene therapy: basic principles and safety considerations. In Principles and Practice of the Biologic Therapy of Cancer, 3rd ed. (Rosenberg, S. A., ed.), Lippincott, New York, pp. 733–747.Google Scholar
  44. 43.
    Pilaro, A. M. (2000, November 17) Preclinical animal models in gene therapy research. Biological Response Modifiers Advisory Committee Meeting. Available on-line at:
  45. 44.
    Pacini, D. L., Dubovi, E. J., and Clyde, W. A. Jr. (1984) A new animal model for human respiratory tract disease due to adenovirus. J. Infect. Dis. 150, 92–97.PubMedGoogle Scholar
  46. 45.
    Whitley, R. (2000, November 16) Use of Aotus monkey to assess neurovirulence of replication-selective herpes vectors. Biological Response Modifiers Advisory Committee Meeting. Available on-line at:
  47. 46.
    Lewandowski, G., Zimmerman, M. N., Denk, L. L., Porter, D. D., and Prince, G. A. (2002) Herpes simplex type 1 infects and establishes latency in the brain and trigeminal ganglia during primary infection of the lip in cotton rats and mice. Arch. Virol. 147, 167–179.PubMedCrossRefGoogle Scholar
  48. 47.
    Torres, J. M., Alonso, C., Ortega, A., Mittal, S., Graham, F., and Enjuanes, L. (1996) Tropism of human adenovirus type 5-based vectors in swine and their ability to protect against transmissible gastroenteritis coronavirus. J. Virol. 70, 3770–3780.PubMedGoogle Scholar
  49. 48.
    Morrissey, R. E., Horvath C., Snyder, E. A., et al. (2002) Porcine toxicology studies of SCH 58500, an adenoviral vector for the p53 gene. Toxicol. Sci. 65, 256–265.PubMedCrossRefGoogle Scholar
  50. 49.
    Prince, G. A., Porter, D. D., Jenson, A. B., Horswood, R. L., Chanock, R. M., and Ginsberg, H. S. (1993) Pathogenesis of adenovirus type 5 pneumonia in cotton rats (Sigmodon hispidus). J. Virol. 67, 101–111.PubMedGoogle Scholar
  51. 50.
    Prince, G. A. (1994) The cotton rat in biomedical research. Animal Welfare Information Center Newslett. 5. Available on-line at:
  52. 51.
    Ward, L. E. (2001) Handling the cotton rat for research. Lab. Anim. 30, 45–50.Google Scholar
  53. 52.
    Ginsberg, H. S., Lundholm-Beauchamp, U., Horswood, R. L., et al. (1989) Role of early region 3 (E3) in pathogenesis of adenovirus disease. Proc. Natl. Acad. Sci. USA 86, 3823–3827.PubMedCrossRefGoogle Scholar
  54. 53.
    Berencsi, K., Uri, A., Valyi-Nagy, T., et al. (1994) Early region 3-replacement adenovirus recombinants are less pathogenic in cotton rats and mice than early region 3-deleted viruses. Lab. Invest. 71, 350–358.PubMedGoogle Scholar
  55. 54.
    Smith, J. G., Raper, S. E., Wheeldon, E. B., et al. (1997) Intracranial administration of adenovirus expressing HSV-TK in combination with ganciclovir produces a dose-dependent, self limiting inflammatory response. Hum. Gene Ther. 8, 943–954.PubMedGoogle Scholar
  56. 55.
    Rojas-Martinez, A., Wyde, P. R., Montgomery, C. A., Chen, S. H., Woo, S. L., and Aguilar-Cordova, E. (1998) Distribution, persistency, toxicity, and lack of replication of an E1A-deficient adenoviral vector after intracardiac delivery in the cotton rat. Cancer Gene Ther. 5, 365–370.PubMedGoogle Scholar
  57. 56.
    Wildner, O. and Morris, J. C. (2002) Subcutaneous administration of a replication-competent adenovirus expressing HSV-tk to cotton rats: dissemination, dersistence, shedding, and pathogenicity. Hum. Gene Ther. 13, 101–112.PubMedCrossRefGoogle Scholar
  58. 57.
    Barahona, H., Melendez, L. V., Hunt, R. D., and Daniel, M. D. (1976) The owl monkey (Aotus trivirgatus) as an animal model for viral diseases and oncologic studies. Lab. Anim. Sci. 26, 1104–1112.PubMedGoogle Scholar
  59. 58.
    Leib, D. A., Hart, C. A., and McCarthy, K. (1987) Characterization of four herpesviruses isolated from owl monkeys and their comparison with Herpesvirus saimiri type 1 (Herpesvirus tamarinus) and herpes simplex virus type 1. J. Comp. Pathol. 97, 159–169.PubMedCrossRefGoogle Scholar
  60. 59.
    Meignier, B., Jourdier, T. M., Norrild, B., Pereira, L., and Roizman, B. (1987) Immunization of experimental animals with reconstituted glycoprotein mixtures of herpes simplex virus 1 and 2: protection against challenge with virulent virus. J. Infect. Dis. 155, 921–930.PubMedGoogle Scholar
  61. 60.
    Meignier, B., Martin, B., Whitley, R. J., and Roizman, B. (1990) In vivo behavior of genetically engineered herpes simplex viruses R7017 and R7020. II. Studies in immunocompetent and immunosuppressed owl monkeys (Aotus trivirgatus). J. Infect. Dis. 162, 313–321.PubMedGoogle Scholar
  62. 61.
    Hunter, W. D., Martuza, R. L., Feigenbaum, F., et al. (1999) Attenuated, replication-competent herpes simplex virus type 1 mutant G207: safety evaluation of intracerebral injection in nonhuman primates. J. Virol. 73, 6319–6326.PubMedGoogle Scholar
  63. 62.
    Todo, T., Feigenbaum, F., Rabkin, S. D., et al. (2000) Viral shedding and biodistribution of G207, a multimutated, conditionally replicating herpes simplex virus type 1, after intracerebral inoculation in Aotus. Mol. Ther. 2, 588–595.PubMedCrossRefGoogle Scholar
  64. 63.
    Varghese, S., Newsome, J. T., Rabkin, S. D., et al. (2001) Preclinical safety evaluation of G207, a replication-competent herpes simplex virus type 1, inoculated intraprostatically in mice and nonhuman primates. Hum. Gene Ther. 12, 999–1010.PubMedCrossRefGoogle Scholar
  65. 64.
    Sundaresan, P., Hunter, W. D., Martuza, R. L., and Rabkin, S. D. (2000) Attenuated, replication-competent herpes simplex virus type 1 mutant G207: safety evaluation in mice. J. Virol. 74, 3832–3841.PubMedCrossRefGoogle Scholar
  66. 65.
    Olson, H., Betton, G., Robinson, D., et al. (2000) Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul. Toxicol. Pharmacol. 32, 56–67.PubMedCrossRefGoogle Scholar
  67. 66.
    Freireich, E. J., Gehan, E. A., Rall, D. P., Schmidt, L. H., and Skipper, H. E. (1966) Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man. Cancer Chemother. Rep. 50, 219–244.PubMedGoogle Scholar
  68. 67.
    Lozier, J. N., Metzger, M. E., Donahue, R. E., and Morgan, R. A. (1999) The rhesus macaque as an animal model for hemophilia B gene therapy. Blood 93, 1875–1881.PubMedGoogle Scholar
  69. 68.
    Lozier, J. N., Metzger, M. E., Donahue, R. E., and Morgan, R. A. (1999) Adenovirus-mediated expression of human coagulation factor IX in the rhesus macaque is associated with dose-limiting toxicity. Blood 94, 3968–3975.PubMedGoogle Scholar
  70. 69.
    Eckardt, L., Haverkamp, W., Borggrefe, M., and Breithardt, G. (1998) Experimental models of torsade de pointes. Cardiovasc. Res. 39, 178–193.PubMedCrossRefGoogle Scholar
  71. 70.
    Eckardt, L., Haverkamp, W., Mertens, H., et al. (1998) Drug-related torsade de pointes in the isolated rabbit heart: comparison of clofilium, d,l-sotalol and erythromycin. J. Cardiovasc. Pharmacol. 32, 425–434.PubMedCrossRefGoogle Scholar
  72. 71.
    Jaffe, A. S. (2001) Elevations in cardiac troponin measurements: false false-positives: the real truth. Cardiovasc. Toxicol. 1, 87–92.PubMedCrossRefGoogle Scholar
  73. 72.
    Sparano, J. A., Brown, D. L., and Wolff, A. C. (2002) Predicting cancer therapy-induced cardiotoxicity: the role of troponins and other markers. Drug Saf. 25, 301–311.PubMedCrossRefGoogle Scholar
  74. 73.
    Serabian, M. A. and Pilaro, A. M. (2000, November 17) Preclinical considerations for gene transfer clinical trials: vector biodistribution. Biological Response Modifiers Advisory Committee Meeting. Available on-line at:
  75. 74.
    Goodman, J. C., Trask, T. W., Chen, S. H., et al. (1996) Adenoviral-mediated thymidine kinase gene transfer into the primate brain followed by systemic ganciclovir: pathologic, radiologic, and molecular studies. Hum. Gene Ther. 7, 1241–1250.PubMedGoogle Scholar
  76. 75.
    Recombinant DNA Advisory Committee (RAC), National Institutes of Health (1999, March 11–12). Meeting summary (available on-line at: and meeting minutes RAC Minutes-03/11–12/99. Available on-line at: RAC.htm.
  77. 76.
    Snell, G. D., Hummel, K. P., and Abelmann, W. H. (1944) A technique for the artificial insemination of mice. Anat. Rec. 90, 243–253.CrossRefGoogle Scholar
  78. 77.
    Kile, J. C. Jr. (1951) An improved method for the artificial insemination of mice. Anat. Rec. 109, 109–117.PubMedCrossRefGoogle Scholar
  79. 78.
    Donahue, R. E., Kessler, S. W., Bodine, D., et al. (1992) Helper virus induced T cell lymphoma in nonhuman primates after retroviral mediated gene transfer. J. Exp. Med. 176, 1125–1135.PubMedCrossRefGoogle Scholar
  80. 79.
    Zahradnik, J. M., Spencer, M. J., and Porter, D. D. (1980) Adenovirus infection in the immunocompromised patient. Am. J. Med. 68, 725–732.PubMedCrossRefGoogle Scholar
  81. 80.
    Haura, E. B., Winden, M. A., Proia, A. D., and Trotter, J. E. (2002) Fulminant hepatic failure due to disseminated adenovirus infection in a patient with chronic lymphocytic leukemia. Cancer Control 9, 248–253.PubMedGoogle Scholar
  82. 81.
    Lozier, J. N., Csako, G., Mondoro, T. H., et al. (2002) Toxicity of a first-generation adenoviral vector in rhesus macaques. Hum. Gene Ther. 13, 113–124.PubMedCrossRefGoogle Scholar
  83. 82.
    Morral, N., O’Neal, W. K., Rice, K., et al. (2002) Lethal toxicity, severe endothelial injury, and a threshold effect with high doses of an adenoviral vector in baboons. Hum. Gene Ther. 13, 143–154.PubMedCrossRefGoogle Scholar
  84. 83.
    Nunes, F. A., Furth, E. E., Wilson, J. M., and Raper, S. E. (1999) Gene transfer into the liver of nonhuman primates with E1-deleted recombinant adenoviral vectors: safety of readministration. Hum. Gene Ther. 10, 2515–2526.PubMedCrossRefGoogle Scholar
  85. 84.
    Sullivan, D. E., Dash, S., Du, H., et al. (1997) Liver-directed gene transfer in non-human primates. Hum. Gene Ther. 8, 1195–1206.PubMedGoogle Scholar
  86. 85.
    Simon, R. H., Engelhardt, J. F., Yang, Y., et al. (1993) Adenovirus-mediated transfer of the CFTR gene to lung of nonhuman primates: toxicity study. Hum. Gene Ther. 4, 771–780.PubMedGoogle Scholar
  87. 86.
    Yang, Y., Su, Q., and Wilson, J. M. (1996) Role of viral antigens in destructive cellular immune responses to adenovirus vector-transduced cells in mouse lungs. J. Virol. 70, 7209–7212.PubMedGoogle Scholar
  88. 87.
    Yang, Y. and Wilson, J. M. (1995) Clearance of adenovirus-infected hepatocytes by MHC class I-restricted CD4+ CTLs in vivo. J. Immunol. 155, 2564–2570.PubMedGoogle Scholar
  89. 88.
    Mack, C. A., Song, W. R., Carpenter, H., et al. (1997) Circumvention of anti-adenovirus neutralizing immunity by administration of an adenoviral vector of an alternate serotype. Hum. Gene Ther. 8, 99–109.PubMedGoogle Scholar
  90. 89.
    Harvey, B. G., Maroni, J., O’Donoghue, K. A., et al. (2002) Safety of local delivery of low-and intermediate-dose adenovirus gene transfer vectors to individuals with a spectrum of morbid conditions. Hum. Gene Ther. 13, 15–63.PubMedCrossRefGoogle Scholar
  91. 90.
    Brann, T., Kayda, D., Lyons, R. M., et al. (1999) Adenoviral vector-mediated expression of physiologic levels of human factor VIII in nonhuman primates. Hum. Gene Ther. 10, 299–301.CrossRefGoogle Scholar
  92. 91.
    Raper, S. E., Haskal, Z. J., Ye, X., et al. (1998) Selective gene transfer into the liver of non-human primates with E1-deleted, E2A-defective, or E1–E4 deleted recombinant adenoviruses. Hum. Gene Ther. 9, 671–679.PubMedGoogle Scholar
  93. 92.
    O’Neal, W. K., Zhou, H., Morral, N., et al. (1998) Toxicological comparison of E2a-deleted and first-generation adenoviral vectors expressing alpha1-antitrypsin after systemic delivery. Hum. Gene Ther. 9, 1587–1598.PubMedGoogle Scholar
  94. 93.
    Batshaw, M. L., Wilson, J. M., Raper, S., Yudkoff, M., and Robinson, M. B. (1999) Recombinant adenovirus gene transfer in adults with partial ornithine transcarbamylase deficiency (OTCD). Hum. Gene Ther. 10, 2419–2437.PubMedCrossRefGoogle Scholar
  95. 94.
    Wickham, T. J., Carrion, M. E., and Kovesdi, I. (1995) Targeting of adenovirus penton base to new receptors through replacement of its RGD motif with other receptor-specific peptide motifs. Gene Ther. 2, 750–756.PubMedGoogle Scholar
  96. 95.
    Krasnykh, V. N., Mikheeva, G. V., Douglas, J. T., and Curiel, D. T. (1996) Generation of recombinant adenovirus vectors with modified fibers for altering viral tropism. J. Virol. 70, 6839–6846.PubMedGoogle Scholar
  97. 96.
    Miller, R. and Curiel, D. T. (1996) Towards the use of replicative adenoviral vectors for cancer gene therapy. Gene Ther. 3, 557–559.PubMedGoogle Scholar
  98. 97.
    Wickham, T. J., Segal, D. M., Roelvink, P. W., et al. (1996) Targeted adenovirus gene transfer to endothelial and smooth muscle cells by using bispecific antibodies. J. Virol. 70, 6831–6838.PubMedGoogle Scholar
  99. 98.
    Kochanek, S., Clemens, P. R., Mitani, K., Chen, H. H., Chan, S., and Caskey, C. T. (1996) A new adenoviral vector: replacement of all viral coding sequences with 28 kb of DNA independently expressing both full-length dystrophin and β-galactosidase. Proc. Natl. Acad. Sci. USA 93, 5731–5736.PubMedCrossRefGoogle Scholar
  100. 99.
    Siegl, G., Bates, R. C., Berns, K. I., et al. (1985) Characteristics and taxonomy of Parvoviridae. Intervirology 23, 61–73.PubMedGoogle Scholar
  101. 100.
    Atchison, R. W., Casto, B. C., and Hammon, W. McD. (1965) Adenovirus-associated defective virus particles. Science 194, 754–756.CrossRefGoogle Scholar
  102. 101.
    Buller, R. M., Janik, J. E., Sebring, E. D., and Rose, J. A. (1981) Herpes simplex virus types 1 and 2 completely help adenovirus-associated virus replication. J. Virol. 40, 241–247.PubMedGoogle Scholar
  103. 102.
    Kotin, R. (1994) Prospects for the use of adeno-associated virus as a vector for human gene therapy. Hum. Gene Ther. 5, 793–801.PubMedGoogle Scholar
  104. 103.
    Flotte, T. R. and Carter, B. J. (1995) Adeno-associated virus vectors for gene therapy. Gene Ther. 2, 357–362.PubMedGoogle Scholar
  105. 104.
    Flotte, T. R., Afione, S. A., Conrad, C., et al. (1993) Stable in vivo expression of the cystic fibrosis transmembrane conductance regulator with an adeno-associated virus vector. Proc. Natl. Acad. Sci. USA 90, 10,613–10,617.PubMedCrossRefGoogle Scholar
  106. 105.
    Kotin, R. M., Siniscalco, M., Samulski, R. J., et al. (1990) Site-specific integration by adeno-associated virus. Proc. Natl. Acad. Sci. USA 87, 2211–2215.PubMedCrossRefGoogle Scholar
  107. 106.
    Kotin, R. M., Menninger, J. C., Ward, D. C., and Berns, K. I. (1991) Mapping and direct visualisation of region-specific viral DNA integration site on chromosome 19q13-qter. Genomics 10, 831–834.PubMedCrossRefGoogle Scholar
  108. 107.
    Blacklow, N. R., Hoggan, M. D., Kapikian, A. Z., Austin, J. B., and Rowe, W. P. (1968) Epidemiology of adeno-associated virus infection in a nursery population. Am. J. Epidemiol. 88, 368–378.PubMedGoogle Scholar
  109. 108.
    Blacklow, N. R., Hoggan, M. D., Sereno, M. S., et al. (1971) A seroepidemiologic study of adenovirus-associated virus infection in infants and children. Am. J. Epidemiol. 94, 359–366.PubMedGoogle Scholar
  110. 109.
    Blacklow, N. R. (1988) Adeno-associated viruses of humans. In Parvoviruses and Human Disease (Pattison, J., ed.), CRC Press, Boca Raton, FL, pp. 165–174.Google Scholar
  111. 110.
    Chiorini, A., Wendtner, C. M., Urcelay, H., Saffer, B., Hallek, N., and Kotin, R. M. (1995) High efficiency transfer of the T cell co-stimulatory molecule B7-2 to lymphoid cells using high-titer recombinant adeno-associated virus vectors. Hum. Gene Ther. 6, 1531–1541.PubMedGoogle Scholar
  112. 111.
    Walsh, C. E., Liu, J. M., Xiao, X., Young, N. S., Nienhuis, A. W., and Samulski, R. J. (1992) Regulated high level expression of a human γ-globin gene introduced into erythroid cells by an adeno-associated virus vector. Proc. Natl. Acad. Sci. USA 89, 7257–7261.PubMedCrossRefGoogle Scholar
  113. 112.
    Flotte, T. R., Conrad, C., Reynolds, T., et al. (1995) Preclinical evaluation of AAV vectors expressing the human CTFR cDNA [abstract]. J. Cell Biochem. 21A, 364.Google Scholar
  114. 113.
    Robbins, P. D., Tahara, H., Mueller, G., et al. (1994) Retroviral vectors for use in human gene therapy for cancer, Gaucher disease, and arthritis. Ann. NY Acad. Sci. 716, 72–88.PubMedCrossRefGoogle Scholar
  115. 114.
    Riviere, I., Brose, K., and Mulligan, R. C. (1995) Effects of retroviral vector design on expression of human adenosine deaminase in murine bone marrow transplant recipients engrafted with genetically modified cells. Proc. Natl. Acad. Sci. USA 92, 6733–6737.PubMedCrossRefGoogle Scholar
  116. 115.
    Cornetta, K. (1992) Safety aspects of gene therapy. Br. J. Haematol. 80, 421–426.PubMedGoogle Scholar
  117. 116.
    Wilson, C. A., Ng, T.-H., and Miller, A. E. (1997) Evaluation of recommendations for replication competent retrovirus testing associated with use of retroviral vectors. Hum. Gene Ther. 8, 869–874.PubMedCrossRefGoogle Scholar
  118. 117.
    Hacein-Bey-Abina, S., Le Deist, F., Carlier, F., et al. (2002) Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. N. Engl. J. Med. 346, 1185–1193.PubMedCrossRefGoogle Scholar
  119. 118.
    Kim, V. N., Mitrophanous, K., Kingsman, S. M., and Kingsman, A. J. (1998) Minimal requirement for a lentivirus vector based on human immunodeficiency virus type 1. J. Virol. 72, 811–816.PubMedGoogle Scholar
  120. 119.
    Miyoshi, H., Blomer, U., Takahashi, M., Gage, F. H., and Verma, I. M. (1998) Development of a self-inactivating lentivirus vector. J. Virol. 72, 8150–8157.PubMedGoogle Scholar
  121. 120.
    Mitta, B., Rimann, M., Ehrengruber, M. U., et al. (2002) Advanced modular self-inactivating lentiviral expression vectors for multigene interventions in mammalian cells and in vivo transduction. Nucleic Acids Res. 30, e113.PubMedCrossRefGoogle Scholar
  122. 121.
    Koya, R. C., Kasahara, N., Pullarkat, V., Levine, A. M., and Stripecke, R. (2002) Transduction of acute myeloid leukemia cells with third generation self-inactivating lentiviral vectors expressing CD80 and GM-CSF: effects on proliferation, differentiation, and stimulation of allogeneic and autologous anti-leukemia immune responses. Leukemia 16, 1645–1654.PubMedCrossRefGoogle Scholar
  123. 122.
    Zufferey, R., Dull, T., Mandel, R. J., et al. (1998) Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery. J. Virol. 72, 9873–9880.PubMedGoogle Scholar
  124. 123.
    Cheng, L., Chaidhawangul, S., Wong-Staal, F., et al. (2002) Human immunodeficiency virus type 2 (HIV-2) vector-mediated in vivo gene transfer into adult rabbit retina. Curr. Eye Res. 24, 196–201.PubMedCrossRefGoogle Scholar
  125. 124.
    Kobayashi, M., Iida, A., Ueda, Y., and Hasegawa, M. (2003) Pseudotyped lentivirus vectors derived from simian immunodeficiency virus SIVagm with envelope glycoproteins from paramyxovirus. J. Virol. 77, 2607–2614.PubMedCrossRefGoogle Scholar
  126. 125.
    Berkowitz, R., Ilves, H., Lin, W. Y., et al. (2001) Construction and molecular analysis of gene transfer systems derived from bovine immunodeficiency virus. J. Virol. 75, 3371–3382.PubMedCrossRefGoogle Scholar
  127. 126.
    Molina, R. P., Matukonis, M., Paszkiet, B., Zhang, J., Kaleko, M., and Luo, T. (2002) Mapping of the bovine immunodeficiency virus packaging signal and RRE and incorporation into a minimal gene transfer vector. Virology 304, 10–23.PubMedCrossRefGoogle Scholar
  128. 127.
    Lotery, A. J., Derksen, T. A., Russell, S. R., et al. (2002) Gene transfer to the nonhuman primate retina with recombinant feline immunodeficiency virus vectors. Hum. Gene Ther. 13, 689–696.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2005

Authors and Affiliations

  • Rosemarie Aurigemma
    • 1
  • Joseph E. Tomaszewski
    • 2
  • Sheryl Ruppel
    • 3
  • Stephen Creekmore
    • 1
  • Edward A. Sausville
    • 4
  1. 1.Biological Resources Branch, Developmental Therapeutics ProgramNational Cancer Institute, NCI-FrederickFrederick
  2. 2.Toxicology & Pharmacology Branch, Developmental Therapeutics ProgramNational Cancer InstituteBethesda
  3. 3.Biological Resources Branch, Developmental Therapeutics ProgramNational Cancer InstituteBethesda
  4. 4.Biopharmaceutical Development ProgramSAID-Frederick/NCI-FrederickFrederick

Personalised recommendations