Abstract
Adenovirus (Ad) vectors have been used to successfully deliver genes into a wide variety of non-central nervous system (CNS) tissues and organs in animal models of human disease and in several human phase I clinical trials (1–3). Adenoviruses are easily purified to the high titers required for in vivo administration and they are efficient in transducing terminally differentiated cells such as neurons and glial cells, resulting in high levels of transgene expression and spatially restricted transgene expression within the region of virus administration. To date, most vectors utilized have been first-generation partially deleted vectors. The most commonly used have been E1/E3-deleted vectors, or second- and third-generation vectors with further deletions in E2 orE4.
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Crystal, R. G., McElvany, N. G., Rosenfeld, M. A., Chu, C. S., Mastrangeli, A., Hay, J. G., et al. (1994) Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis. Nature Genet. 8, 42–51.
Knowles, M. R., Hohneker, K. W., Zhou, Z., Olsen, J. C., Noah, T. L., Hu, P-C., et al. (1995) A controlled study of adenoviral-vector-mediated gene transfer in the nasal epithelium of patients with cystic fibrosis. N. Engl. J. Med. 333, 823–831.
Gahery-Segard, H., Molinier-Frenkel, V., Le Boulaire, C., Saulnier, P., Opolon, P., Lengagne, R., et al. (1997) Phase I trial of recombinant adenovirus gene transfer in lung cancer. Longitudinal study of the immune responses to transgene and viral products. J. Clin. Invest. 100, 2218–2226.
Yang, Y., Ertl, H. C. J., and Wilson, J. M. (1994) MHC class-I restricted cytotoxic T-lymphocytes to viral antigens destroy hepatocytes in mice infected with E1-deleted recombinant adenoviruses. Immunity 1, 433–442.
Yang, Y., Li, Q., Ertl, H. C. J., and Wilson, J. M. (1995) Cellular and humoral immune responses to viral antigens create barriers to lung-directed gene therapy with recombinant adenoviruses. J. Virol. 69, 2004–2015.
Byrnes, A. P., Rusby, J. E., Wood, M. J. A., and Charlton, H. M. (1995) Adenovirus gene transfer causes inflammation in the brain. Neuroscience 66, 1015–1024.
Byrnes, A. P., MacLaren, R. E., and Charlton, H. M. (1996a) Immunological instability of persistent adenovirus vectors in the brain: Peripheral exposure to vector leads to renewed inflammation, reduced gene expression and demyelination. J. Neurosci. 16, 3045–3055.
Byrnes, A. P., Wood, M. J. A., and Charlton, H. M. (1996b) Role of T cells in inflammation caused by adenovirus vectors in the brain. Gene Ther. 3, 644–651.
Dewey, R. A., Morrissey, G., Cowsill, C. M., Stone, D., Bolognani, F., Dodd, N. J. F., et al. (1999) Chronic brain inflammation and persistent herpes simplex virus 1 thymidine kinase expression in survivors of syngenic glioma treated by adenovirus-mediated gene therapy: Implications for clinical trials. Nature Med. 5, 1256–1263.
Gerdes, C. A., Castro, M. G., and Lowenstein, P. R. (2000) Strong promoters are the key to highly efficient, non-inflammatory and non-cytotoxic adenoviralmediated transgene delivery into the brain in vivo. Mol. Ther. 2, 330–338.
Thomas, C.E., Schiedner, G., Kochanek, S., Castro, M. G., and Lowenstein, P. R. (2000) Peripheral infection with adenovirus causes unexpected long term brain inflammation in animals injected intracranially with first generation, but not with high capacity adenovirus vectors: Towards realistic long term neurological gene therapy for chronic diseases. Proc. Natl. Acad. Sci. USA 97, 7482–7487.
Trask, T. W., Trask, R. P., Aguilar-Cordova, E., Shine, H. D., Wyde, P. R., Goodman, J. C., et al. (2000) Phase I study of adenoviral delivery of the HSV-tk gene and ganciclovir administration in patients with recurrent malignant brain tumors. Mol. Ther. 1, 195–203.
Thomas, C. E., Birkett, D., Anozie, I., Castro, M. G., and Lowenstein, P. R. (2001a) Acute direct adenoviral vector cytotoxicity and chronic, but not acute, inflammatory responses correlate with decreased vector-mediated transgene expression in the brain. Mol. Ther. 3, 36–46.
Wood, M. J. A., Charlton, H. M., Wood, K. J., Kajiwara, K., and Byrnes, A. P. (1996a) Immune responses to adenovirus vectors in the nervous system. Trends Neurosci. 19, 497–501.
Wood, M. J. A., Byrnes, A. P., McMenamin, M., Kajiwara, K., Vine, A., Gordon, I., et al. (1996b) Immune responses to viruses: Practical implications for the use of viruses as vectors for experimental and clinical gene therapy, in Protocols for Gene Transfer in Neuroscience (Lowenstein, P. R. and Enquist, L. W., eds), Wiley, New York, pp. 365–376.
Cartmell, T., Southgate, T., Rees, G. S., Castro, M. G., Lowenstein, P. R., and Luheshi, G. N. (1999) Interleukin-1 mediates a rapid inflammatory response after injection of adenoviral vectors into the brain. J. Neurosci. 19, 1517–1523.
Benihoud, K., Yeh, P., and Perricaudet, M. (1999) Adenovirus vectors for gene delivery. Curr. Opin. Biotechnol. 10, 440–447.
Ohmoto, Y., Wood, M. J. A., Charlton, H. M., Kajiwara, K., Perry, V. H., and Wood, K. J. (1999) Variation in the immune response to adenoviral vectors in the brain: influence of mouse strain, environmental conditions and priming. Gene Ther. 6, 471–481.
Mitani, K., Graham, F. L., Caskey, C. T., and Kochanek, S. (1995) Rescue, propagation, and partial purification of a helper virus-dependent adenovirus vector. Proc. Natl. Acad. Sci. USA 92, 3854–3858.
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 beta-galactosidase. Proc. Natl. Acad. Sci. USA 93, 5731–5736.
Parks, R. J., Chen, L., Anton, M., Sankar, U., Rudnicki, M. A., and Graham, F. L. (1996) A helper-dependent adenovirus vector system: Removal of helper virus by Cre-mediated excision of the viral packaging signal. Proc. Natl. Acad. Sci. USA 93, 13,565–13,570.
Wang, X., Zhang, G. R., Yang, T., Zhang, W., and Geller, A. I. (2000) Fifty-one kilobase HSV-1 plasmid vector can be packaged using a helper virus free system and supports expression in the rat brain. Biotechniques 1, 102–107.
Chen, H. H., Mack, L. M., Kelly, R., Ontell, M., Kochanek, S., and Clemens, P. R. (1997) Persistence in muscle of an adenoviral vector that lacks all viral genes. Proc. Natl. Acad. Sci. USA 94, 1645–1650.
Morral, N., Parks, R. J., Zhou, H., Langston, C., Schiedner, G., Quinones, J., et al. (1998) High doses of a helper-dependent adenoviral vector yield supraphysi-ological levels of α1-antitrypsin with negligible toxicity. Hum. Gene Ther. 9, 2709–2716.
Morsy, M. A., Gu, M., Motzel, S., Zhao, J., Lin, J., Su, Q., et al. (1998) An adenoviral vector deleted for all viral coding sequences results in enhanced safety and expression of the leptin transgene. Proc. Natl. Acad. Sci. USA 95, 7866–7871.
Schiedner, G., Morral, N., Parks, R. J., Wu, Y., Koopmans, S. C., Langston, C., et al. (1998) Genomic DNA transfer with a high-capacity adenovirus vector results in improved in vivo gene expression and decreased toxicity. Nature Genet. 18, 180–183.
Chen, H. H., Mack, L. M., Choi, S. Y., Ontell, M., Kochanek, S., and Clemens, P. R. (1999) DNA from both high-capacity and first-generation adenoviral vectors remains intact in skeletal muscle. Hum. Gene Ther. 10, 365–373.
Morral, N., O’Neal, W., Rice, K., Leland, M., Kaplan, J., Piedra, P. A., et al. (1999) Administration of helper-dependent adenoviral vectors and sequential delivery of different vector serotype for long-term liver-directed gene transfer in baboons. Proc. Natl. Acad. Sci. USA 96, 12,816–12,821.
Maione, D., Wiznerowicz, M., Delmastro, P., Cortese, R., Ciliberto, G., La Monica, N., et al. (2000) Prolonged expression and effective readministration of erythropoetin delivered with a fully deleted adenoviral vector. Hum. Gene Ther. 11, 859–868.
Maione, D., Rocca, C. D., Giannetti, P., D’Arrigo, R., Liberatoscioli, L., Franlin, L. L., et al. (2001) An improved helper-dependent adenoviral vector allows persistent gene expression after intramuscular delivery and overcomes preexisting immunity to adenovirus. Proc. Natl. Acad. Sci. USA 98, 5986–5991.
Thomas, C. E., Schiedner, G., Kochanek, S., Castro, M. G., and Lowenstein, P. R. (2001b) Pre-existing anti-adenoviral immunity is not a barrier to efficient and stable transduction of the brain, mediated by novel high-capacity adenovirus vectors. Hum. Gene Ther. 12, 839–846.
Burcin, M. M, Schiedner, G., Kochanek, S., Tsai, S. Y., and O’Malley, B. W. (1999) Adenovirus-mediated regulable target gene expression in vivo. Proc. Natl. Acad. Sci. USA 96, 355–360.
Smith-Arica, J., Morelli, A. E., Larregina, A. T., Smith, J., Lowenstein, P. R., and Castro, M. G. (2000) Cell-type-specific and regulatable transgenesis in the adult brain: adenovirus-encoded combined transcriptional targeting and inducible transgene expression. Mol. Ther. 2, 579–587.
Sandig, V., Youil, R., Bett, A. J., Franlin, L. L., Oshima, M., Maione, D., et al. (2000) Optimization of the helper-dependent adenovirus system for production and potency in vivo. Proc. Natl. Acad. Sci. USA 97, 1002–1007.
Ringrose, L., Lounnas, V., Ehrlich, L., Buchholz, F., Wade, R., and Stewart, A. E (1998) Comparative kinetic analysis of FLP and Cre recombinases: mathematical models for DNA binding and recombination. J. Mol. Biol. 284, 363–384.
Buchholz, F., Angrand, P. O., and Stewart, A. E (1998) Improved properties of FLP recombinase evolved by cycling mutagenesis. Nat. Biotech. 16, 657–662.
Umana, P., Gerdes, C. A., Davis, J. R. E., Castro, M. G., and Lowenstein, P. R. (2001) Efficient FLPe recombinase enables scalable production of helper-dependent adenoviral vectors with negligible helper-virus contamination. Nature Biotechnol. 19, 582–585.
Southgate, T. D., Kingston, P. A., and Castro, M. G. (2001) Current Protocols in Neuroscience (Crawley, J. N., Gerfen, C. R., McKay, R., Rogawski, M. A., Sibley, D. R., and Skolnick, P., eds.), Wiley, New York, pp. 4.23.1–4.23.40
Thomas, C. E., Abordo-Adesida, E., Maleniak, T. C., Stone, D., Gerdes, G., and Lowenstein, P. R. (2001) Critical parameters for gene transfer into the brain using adenoviral vectors, in Current Protocols in Neuroscience (Crawley, J. N., Gerfen, C. R., McKay, R., Rogawski, M. A., Sibley, D. R., and Skolnick, P., eds.), Wiley, New York, pp. 4.24.1–4.24.36.
Sauer, H. and Oertel, W. H. (1994) Progressive degeneration of nigrostriatal dopamine neurons following intrastriatal terminal lesions with 6-hydroxydopamine: a combined retrograde tracing and immunocytochemical study in the rat. Neuroscience 59, 401–415.
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Hurtado-Lorenzo, A., David, A., Thomas, C., Castro, M.G., Lowenstein, P.R. (2003). Use of Recombinant Adenovirus for Gene Transfer into the Rat Brain. In: Machida, C.A. (eds) Viral Vectors for Gene Therapy. Methods in Molecular Medicine™, vol 76. Humana Press. https://doi.org/10.1385/1-59259-304-6:113
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DOI: https://doi.org/10.1385/1-59259-304-6:113
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