Abstract
One of the challenges of current gene therapy vector development, concerns targeting a therapeutic gene to diseased cells with the aim of achieving sufficient gene expression in the affected tissue, while minimizing toxicity and expression in other tissues. The use of recombinant adenoviruses as vectors for gene therapy is restricted by the widespread distribution of the coxsackie and adenovirus receptor (CAR) (1,2), which allows infection of a range of tissues and precludes specific in vivo targeting. It is now well accepted that there is a dose-dependent toxicity associated with systemic delivery of adenoviral (Ad) vectors, in particular the risk of hepatotoxicity is a major concern (3–6). Thus, development of Ad vectors that can target specific tissues following systemic or minimally invasive administration would enhance their therapeutic potential and expand their application. Targeting can be achieved at the level of capsid binding or at later transduction events by the use of tissue-specific promoters (7–10). Targeting at the level of binding is preferred because even the interaction of cells with empty capsids leads to toxic effects (11), however a combination of both strategies has its obvious advantages.
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Bergelson, J. M., Cunningham, J. A., Droguett, G., Kurt-Jones, E. A., Krithivas, A., Hong, J. S., et al. (1997) Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5. Science 275, 1320–1323.
Tomko, R. P. Xu, R., and Philipson, L. (1997) HCAR and MCAR: the human and mouse cellular receptors for subgroup C adenoviruses and group B coxsackieviruses. Proc. Natl. Acad. Sci. USA 94, 3352–3356.
Zhang, Y. Chirmule, N. Gao, G. P. Qian, R. Croyle, M. Joshi, B., et al. (2001) Acute cytokine response to systemic adenoviral vectors in mice is mediated by dendritic cells and macrophages. Mol. Ther. 3, 697–707.
Morral, N. O’Neal, W. K., Rice, K., Leland, M. M., Piedra, P. A., Aguilar-Cordova, E., 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.
Higginbotham, J. N. Seth, P. Blaese, R. M., and Ramsey, W. J. (2002) The release of inflammatory cytokines from human peripheral blood mononuclear cells in vitro following exposure to adenovirus variants and capsid. Hum. Gene Ther. 13, 129–141.
Raper, S. E. Yudkoff, M. Chirmule, N. Gao, G. P. Nunes, F. Haskal, Z. J., et al. (2002) A pilot study of in vivo liver-directed gene transfer with an adenoviral vector in partial ornithine transcarbamylase deficiency. Hum. Gene Ther. 13, 163–175.
Connelly, S. Gardner, J. M. McClelland, A., and Kaleko, M. (1996) High-level tissue specific expression of functional human Factor VIII in mice. Hum. Gene Ther. 7, 183–195.
Pastore, L. Morral, N. Zhou, H. Garcia, R. Parks, R. J. Kochanek, S., et al. (1999) Use of a liver-specific promoter reduces immune response to the transgene in adenoviral vectors. Hum. Gene Ther. 10, 1773–1781.
Bristol, J. A. Gallo-Penn, A. Andrews, J. Idamakanti, N. Kaleko, M., and Connelly, S. (2001) Adenovirus-mediated factor VIII gene expression results in attenuated anti-factor VIII-specific immunity in hemophilia A mice compared with factor VIII protein infusion. Hum. Gene Ther. 12, 1651–1661.
Hartigan-O’Connor, D. Kirk, C. J. Crawford, R. Mule, J. J., and Chamberlain, J. S. (2001) Immune evasion by muscle-specific gene expression in dystrophic muscle. Mol. Ther. 4, 525–533.
Muruve, D. A. Barnes, M. J. Stillman, I. E., and Libermann, T. A. (1999) Adenoviral gene therapy leads to rapid induction of multiple chemokines and acute neutrophil-dependent hepatic injury in vivo. Hum. Gene Ther. 10, 965–976.
Roelvink, P. W. Lizonova, A. Lee, J. G. Li, Y. Bergelson, J. M. Finberg, R. W., et al. (1998) The coxsackievirus-adenovirus receptor protein can function as a cellular attachment protein for adenovirus serotypes from subgroups A, C, D, E, andF. J. Virol. 72, 7909–7915.
Ginsberg, H. S., ed. (1984) The Adenoviruses, Plenum, New York.
Wickham, T. J. Segal, D. M. Roelvink, P. W. Carrion, M. E. Lizonova, A. Lee, G. M., et al. (1996) Targeted adenovirus gene transfer to endothelial and smooth muscle cells by using bispecific antibodies. J. Virol. 70, 6831–6838.
Douglas, J. T. Rogers, B. E. Rosenfeld, M. E. Michael, S. I. Feng, M., and Curiel, D. T. (1996) Targeted gene delivery by tropism-modified adenoviral vectors. Nat. Biotechnol. 14, 1574–1578.
Wickham, T. J. Lee, G. M. Titus, J. A. Sconocchia, G. Bakacs, T. Kovesdi, I., et al. (1997) Targeted adenovirus-mediated gene delivery to T cells via CD3. J. Virol. 71, 7663–7669.
Goldman, C. K. Rogers, B. E. Douglas, J. T., Sosnowski, B. A. Ying, W. Siegal, G. P., et al. (1997) Targeted gene delivery to Kaposi’s sarcoma cells via the fibroblast growth factor receptor. Cancer Res. 57, 1447–1451.
Rogers, B. E. Douglas, J. T. Ahlem, C. Buchsbaum, D. J. Frincke, J., and Curiel, D. T. (1997) Use of a novel cross-linking method to modify adenovirus tropism. Gene Ther. 4, 1387–1392.
Rancourt, C. Rogers, B. E. Sosnowski, B. A. Wang, M. Piche, A. Pierce, G. F., et al. (1998) Basic fibroblast growth factor enhancement of adenovirus-mediated delivery of the herpes simplex virus thymidine kinase gene results in augmented therapeutic benefit in a murine model of ovarian cancer. Clin. Cancer Res. 4, 2455–2461.
Gu, D. L. Gonzalez, A. M. Printz, M. A. Doukas, J. Ying, W. D’Andrea, M., et al. (1999) Fibroblast growth factor 2 retargeted adenovirus has redirected cellular tropism: evidence for reduced toxicity and enhanced antitumor activity in mice. Cancer Res. 59, 2608–2614.
Blackwell, J. L., Miller, C. R., Douglas, J. T., Li, H., Reynolds, P. N., Carroll, W. R., et al. (1999) Retargeting to EGFR enhances adenovirus infection efficiency of squamous cell carcinoma. Arch. Otolaryngol. Head Neck Surg. 125, 856–863.
Doukas, J., Hoganson, D. K., Ong, M., Ying, W., Lacey, D. L., Baird, A., et al. (1999) Retargeted delivery of adenoviral vectors through fibroblast growth factor receptors involves unique cellular pathways. FASEB J. 13, 1459–1466.
Yoon, S. K., Mohr, L., O’Riordan, C. R., Lachapelle, A., Armentano, D., and Wands, J. R. (2000) Targeting a recombinant adenovirus vector to HCC cells using a bifunctional Fab-antibody conjugate. Biochem. Biophys. Res. Commun. 272, 497–504.
Trepel, M., Grifman, M., Weitzman, M. D., and Pasqualini, R. (2000) Molecular adaptors for vascular-targeted adenoviral gene delivery. Hum. Gene Ther. 11, 1971–1981.
Tillman, B. W., Hayes, T. L., DeGruijl, T. D., Douglas, J. T., and Curiel, D. T. (2000) Adenoviral vectors targeted to CD40 enhance the efficacy of dendritic cell-based vaccination against human papillomavirus 16-induced tumor cells in a murine model. Cancer Res. 60, 5456–5463.
Reynolds, P. N., Zinn, K. R., Gavrilyuk, V. D., Balyasnikova, I. V., Rogers, B. E., Buchsbaum, D. J., et al. (2000) A targetable, injectable adenoviral vector for selective gene delivery to pulmonary endothelium in vivo. Mol. Ther. 2, 562–578.
Ebbinghaus, C., Al-Jaibaji, A., Operschall, E., Schoffel, A., Peter, I., Greber, U. F., et al. (2001) Functional and selective targeting of adenovirus to high-affinity Fc gamma receptor I-positive cells by using a bispecific hybrid adapter. J. Virol. 75, 480–489.
Hoganson, D. K., Sosnowski, B. A., Pierce, G. F., and Doukas, J. (2001) Uptake of adenoviral vectors via fibroblast growth factor receptors involves intracellular pathways that differ from the targeting ligand. Mol. Ther. 3, 105–112.
Grill, J., Van Beusechem, V. W., Van Der Valk, P., Dirven, C. M., Leonhart, A., Pherai, D. S., et al. (2001) Combined targeting of adenoviruses to integrins and epidermal growth factor receptors increases gene transfer into primary glioma cells and spheroids. Clin. Cancer Res. 7, 641–650.
Nettelbeck, D. M., Miller, D. W., Jerome, V., Zuzarte, M., Watkins, S. J., Hawkins, R. E., et al. (2001) Targeting of adenovirus to endothelial cells by a bispecific single-chain diabody directed against the adenovirus fiber knob domain and human endoglin (CD105). Mol. Ther. 3, 882–891.
Israel, B. F., Pickles, R. J., Segal, D. M., Gerard, R. D., and Kenney, S. C. (2001) Enhancement of adenovirus vector entry into CD70-positive B-cell lines by using a bispecific CD70-adenovirus fiber antibody. J. Virol. 75, 5215–5221.
Smith, J. S., Keller, J. R., Lohrey, N. C., McCauslin, C. S., Ortiz, M., Cowan, K., et al. (1999) Redirected infection of directly biotinylated recombinant adenovirus vectors through cell surface receptors and antigens. Proc. Natl. Acad. Sci USA 96, 8855–8860.
Romanczuk, H., Galer, C. E., Zabner, J., Barsomian, G., Wadsworth, S. C., and O’Riordan, C. R. (1999) Modification of an adenoviral vector with biologically selected peptides: a novel strategy for gene delivery to cells of choice. Hum. Gene Ther. 10, 2615–2626.
Romanczuk, H., Galer, C. E., Zabner, J., Barsomian, G., Wadsworth, S. C., and O’Riordan, C. R. (1999) Dressing up adenoviruses to modify their tropism. Hum. Gene Ther. 10, 2575–2576.
Drapkin, P. T., O’Riordan, C. R., Yi, S. M., Chiorini, J. A., Cardella, J., Zabner, J., et al. (2000) Targeting the urokinase plasminogen activator receptor enhances gene transfer to human airway epithelia. J. Clin. Invest. 105, 589–596.
Fisher, K. D., Stallwood, Y., Green, N. K., Ulbrich, K., Mautner, V., and Seymour, L. W. (2001) Polymer-coated adenovirus permits efficient retargeting and evades neutralising antibodies. Gene Ther. 8, 341–348.
Wickham, T. J., Roelvink, P. W., Brough, D. E., and Kovesdi, I. (1996) Adenovirus targeted to heparan-containing receptors increases its gene delivery efficiency to multiple cell types. Nat. Biotechnol. 14, 1570–1573.
Wickham, T. J., Tzeng, E., Shears, L. L., 2nd, Roelvink, P. W., Li, Y., Lee, G. M., et al. (1997) Increased in vitro and in vivo gene transfer by adenovirus vectors containing chimeric fiber proteins. J. Virol. 71, 8221–8229.
Hidaka, C., Milano, E., Leopold, P. L., Bergelson, J. M., Hackett, N. R., Finberg, R. W., et al. (1999) CAR-dependent and CAR-independent pathways of adenovirus vector-mediated gene transfer and expression in human fibroblasts. J. Clin. Invest. 103, 579–587.
Gonzalez, R., Vereecque, R., Wickham, T. J., Vanrumbeke, M., Kovesdi, I., Bauters, F., et al. (1999) Increased gene transfer in acute myeloid leukemic cells by an adenovirus vector containing a modified fiber protein. Gene Ther. 6, 314–320.
McDonald, G. A., Zhu, G., Li, Y., Kovesdi, I., Wickham, T. J., and Sukhatme, V. P. (1999) Efficient adenoviral gene transfer to kidney cortical vasculature utilizing a fiber modified vector. J. Gene Med. 1, 103–110.
Bouri, K., Feero, W. G., Myerburg, M. M., Wickham, T. J., Kovesdi, I., Hoffman, E. P., et al. (1999) Polylysine modification of adenoviral fiber protein enhances muscle cell transduction. Hum. Gene Ther. 10, 1633–1640.
Gonzalez, R., Vereecque, R., Wickham, T. J., Facon, T., Hetuin, D., Kovesdi, I., et al. (1999) Transduction of bone marrow cells by the AdZ.F(pK7) modified adenovirus demonstrates preferential gene transfer in myeloma cells. Hum. Gene Ther. 10, 2709–2717.
Staba, M. J., Wickham, T. J., Kovesdi, I., Hallahan, D, E. (2000) Modifications of the fiber in adenovirus vectors increase tropism for malignant glioma models. Cancer Gene Ther. 7, 13–19.
Li, L., Wickham, T. J., and Keegan, A. D. (2001) Efficient transduction of murine B lymphocytes and B lymphoma lines by modified adenoviral vectors: enhancement via targeting to FcR and heparan-containing proteins. Gene Ther. 8, 938–945.
Reynolds, P., Dmitriev, I., and Curiel, D. (1999) Insertion of an RGD motif into the HI loop of adenovirus fiber protein alters the distribution of transgene expression of the systemically administered vector. Gene Ther. 6, 1336–1339.
Roelvink, P. W., Mi Lee, G., Einfeld, D. A., Kovesdi, I., and Wickham, T. J. (1999) Identification of a conserved receptor-binding site on the fiber proteins of CAR-recognizing adenoviridae. Science 286, 1568–1571.
Einfeld, D. A., Brough, D. E., Roelvink, P. W., Kovesdi, I., and Wickham, T. J. (1999) Construction of a pseudoreceptor that mediates transduction by adenoviruses expressing a ligand in fiber or penton base. J. Virol. 73, 9130–9136.
Nicklin, S. A., Von Seggern, D. J., Work, L. M., Pek, D. C., Dominiczak, A. F., Nemerow, G. R., et al. (2001) Ablating adenovirus type 5 fiber-CAR binding and HI loop insertion of the SIGYPLP peptide generate an endothelial cell-selective adenovirus. Mol. Ther. 4, 534–542.
O’Riordan, C. R., Lachapelle, A., Delgado, C., Parkes, V., Wadsworth, S. C., Smith, A. E., et al. (1999) PEGylation of adenovirus with retention of infectivity and protection from neutralizing antibody in vitro and in vivo. Hum. Gene Ther. 10, 1349–1358.
Croyle, M. A., Chirmule, N., Zhang, Y., and Wilson, J. M. (2001) “Stealth” adenoviruses blunt cell-mediated and humoral immune responses against the virus and allow for significant gene expression upon readministration in the lung. J. Virol. 75, 4792–4801.
Croyle, M. A., Yu, Q. C., and Wilson, J. M. (2000) Development of a rapid method for the PEGylation of adenoviruses with enhanced transduction and improved stability under harsh storage conditions. Hum. Gene Ther. 11, 1713–1722.
Abuchowski, A., McCoy, J. R., Palczuk, N. C., van Es, T., and Davis, F. F. (1977) Effect of covalent attachment of polyethylene glycol on immunogenicity and circulating life of bovine liver catalase. J. Biol. Chem. 252, 3582–3586.
Abuchowski, A., Kazo, G. M., Verhoest, C. R., Jr., Van Es, T., Kafkewitz, D., Nucci, M. L., et al. (1984) Cancer therapy with chemically modified enzymes. I. Antitumor properties of polyethylene glycol-asparaginase conjugates. Cancer Biochem. Biophys. 7, 175–186.
Richter, A. W. and Akerblom, E. (1983) Antibodies against polyethylene glycol produced in animals by immunization with monomethoxy polyethylene glycol modified proteins. Int. Arch. Allergy Appl. Immunol. 70, 124–131.
Delgado, C., Patel, J. N., Francis, G. E., and Fisher, D. (1990) Coupling of poly(ethylene glycol) to albumin under very mild conditions by activation with tresyl chloride: characterization of the conjugate by partitioning in aqueous twophase systems. Biotechnol. Appl. Biochem. 12, 119–128.
Francis, G. E., Fisher, D., Delgado, C., Malik, F., Gardiner, A., and Neale, D. (1998) PEGylation of cytokines and other therapeutic proteins and peptides: the importance of biological optimisation of coupling techniques. Int. J. Hematol. 68, 1–18.
Armentano, D., Zabner, J., Sacks, C., Sookdeo, C. C., Smith, M. P., St George, J. A., et al. (1997) Effect of the E4 region on the persistence of transgene expression from adenovirus vectors. J. Virol. 71, 2408–2416.
Yu, D., Wolf, J. K., Scanlon, M., Price, J. E., and Hung, M. C. (1993) Enhanced c-erbB-2/neu expression in human ovarian cancer cells correlates with more severe malignancy that can be suppressed by E1A. Cancer Res. 53, 891–898.
Graham, F. L., Smiley, J., Russell, W. C., and Nairn, R. (1977) Characteristics of a human cell line transformed by DNA from human adenovirus type 5. J. Gen. Virol. 36, 59–74.
Graham, F. L. and van der Eb, A. J. (1973) A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology 52, 456–467.
Maizel, J. V., Jr., White, D. O., and Scharff, M. D. (1968) The polypeptides of adenovirus. I. Evidence for multiple protein components in the virion and a comparison of types 2, 7A, and 12. Virology 36, 115–125.
Green, M., Pina, M., Kimes, R., Wensik, P., Machattie, L., and Thomas, Jr., C. (1967) Adenovirus DNA. I. Molecular weight and conformation. Proc. Natl. Acad. Sci. USA 57, 1302–1309.
van der Eb, A. J., van Kesteren, L. W., and van Bruggen, E. F. (1969) Structural properties of adenovirus DNA’s. Biochim. Biophys. Acta. 182, 530–541.
Lappi, D. A., Matsunami, R., Martineau, D., and Baird, A. (1993) Reducing the heterogeneity of chemically conjugated targeted toxins: homogeneous basic FGF-saporin. Anal. Biochem. 212, 446–451.
Zhang, J. D., Cousens, L. S., Barr, P. J., and Sprang, S. R. (1991) Three-dimensional structure of human basic fibroblast growth factor, a structural homolog of interleukin 1 beta. Proc. Natl. Acad. Sci. USA 88, 3446–3450.
Heid, C. A., Stevens, J., Livak, K. J., and Williams, P. M. (1996) Real time quantitative PCR. Genome Res. 6, 986–994.
Prage, L., Pettersson, U., Hoglund, S., Lonberg-Holm, K., and Philipson, L. (1970) Structural proteins of adenoviruses. IV. Sequential degradation of the adenovirus type 2 virion. Virology 42, 341–358.
Huyghe, B. G., Liu, X., Sutjipto, S., Sugarman, B. J., Horn, M. T., Shepard, H. M., et al. (1995) Purification of a type 5 recombinant adenovirus encoding human p53 by column chromatography. Hum. Gene Ther. 6, 1403–1416.
O’Riordan, C. R., Lachapelle, A. L., Vincent, K. A., and Wadsworth, S. C. (2000) Scalable chromatographic purification process for recombinant adeno-associated virus (rAAV). J. Gene Med. 2, 444–454.
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O’Riordan, C.R., Song, A., Lanciotti, J. (2003). Strategies to Adapt Adenoviral Vectors for Targeted Delivery. In: Machida, C.A. (eds) Viral Vectors for Gene Therapy. Methods in Molecular Medicine™, vol 76. Humana Press. https://doi.org/10.1385/1-59259-304-6:89
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DOI: https://doi.org/10.1385/1-59259-304-6:89
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