Abstract
Effective repeat administration of adenovirus vectors following intranasal or intravenous delivery is hindered by a strong neutralizing antibody response to the vector. Intramuscular administration of adenovirus vectors elicited a neutralizing antibody response that peaked between 14 and 21 days after infection. However, effective repeat intramuscular administration of adenovirus vectors was not hindered by the presence of neutralizing antibodies in the serum. Surprisingly, β-galactosidase expression in the skeletal muscle of immunized mice was equivalent to that observed in control mice. As expected, these serum neutralizing antibodies effectively blocked repeat administration of adenovirus vectors when delivered via the intravenous route. These results were observed in both C57BL/6 and Balb/c mice and thus do not appear to be strain specific. Successful repeat administration of adenovirus vectors to skeletal muscle has significant implications for the use of adenovirus vectors clinically and for increasing the safety and efficacy of adenovirus vector gene delivery.
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References
Wickham TJ et al. Adenovirus targeted to heparan-containing receptors increases its gene delivery efficiency to multiple cell types Nat Biotechnol 1996 14: 1570–1573
Wickham TJ et al. Increased in vitro and in vivo gene transfer by adenovirus vectors containing chimeric fiber proteins J Virol 1997 71: 8221–8229
Wickham TJ et al. Targeted adenovirus-mediated gene delivery to T cells via CD3 J Virol 1997 71: 7663–7669
Michael SI, Hong JS, Curiel DT, Engler JA . Addition of a short peptide ligand to the adenovirus fiber protein Gene Therapy 1995 2: 660–668
Yang Y et al. Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy Proc Natl Acad Sci USA 1994 91: 4407–4411
Bruder JT, Jie T, McVey DL, Kovesdi I . Expression of gp19K increases the persistence of transgene expression from an adenovirus vector in the mouse lung and liver J Virol 1997 71: 7623–7628
Barr D et al. Strain related variations in adenovirally mediated transgene expression from mouse hepatocytes in vivo: comparisons between immunocompetent and immunodeficient inbred strains Gene Therapy 1995 2: 151–155
Tripathy SK, Black HB, Goldwasser E, Leiden JM . Immune responses to transgene-encoded proteins limit the stability of gene expression after injection of replication-defective adenovirus vectors Nature Med 1996 2: 545–550
Wadsworth SC, Zhou H, Smith AE, Kaplan JM . Adenovirus vector-infected cells can escape adenovirus antigen-specific cytotoxic T-lymphocyte killing in vivo J Virol 1997 71: 5189–5196
Michou AI et al. Adenovirus-mediated gene transfer: influence of transgene, mouse strain and type of immune response on persistence of transgene expression Gene Therapy 1997 4: 473–482
Yang Y, Li Q, Ertl HC, Wilson JM . Cellular and humoral immune responses to viral antigens create barriers to lung-directed gene therapy with recombinant adenoviruses J Virol 1995 69: 2004–2015
Yang Y et al. Immune responses to viral antigens versus transgene product in the elimination of recombinant adenovirus-infected hepatocytes in vivo Gene Therapy 1996 3: 137–144
Yang Y, Greenough K, Wilson JM . Transient immune blockade prevents formation of neutralizing antibody to recombinant adenovirus and allows repeated gene transfer to mouse liver Gene Therapy 1996 3: 412–420
McClane SJ, Chirmule N, Burke CV, Raper SE . Characterization of the immune response after local delivery of recombinant adenovirus in murine pancreas and successful strategies for readministration Hum Gene Ther 1997 8: 2207–2216
Lei D et al. Nondepleting anti-CD4 antibody treatment prolongs lung-directed E1-deleted adenovirus-mediated gene expression in rats Hum Gene Ther 1996 7: 2273–2279
Kolls JK et al. Use of transient CD4 lymphocyte depletion to prolong transgene expression of E1-deleted adenoviral vectors Hum Gene Ther 1996 7: 489–497
Yang Y et al. Transient subversion of CD40 ligand function diminishes immune responses to adenovirus vectors in mouse liver and lung tissues J Virol 1996 70: 6370–6377
Kay MA et al. Long-term hepatic adenovirus-mediated gene expression in mice following CTLA4lg administration Nat Genet 1995 11: 191–197
Kjellen L, Pereira HG . Role of adenovirus antigens in the induction of virus neutralizing antibody J Gen Virol 1968 2: 177–185
Wohlfart CE, Svensson UK, Everitt E . Interaction between HeLa cells and adenovirus type 2 virions neutralized by different antisera J Virol 1985 56: 896–903
Wohlfart C . Neutralization of adenoviruses: kinetics, stoichiometry, and mechanisms J Virol 1988 62: 2321–2328
Horwitz MS . Adenoviridae and their replication. In: Fields BN et al (eds) Virology Raven Press: New York 1990 pp 1679–1721
Kass-Eisler A et al. Circumventing the immune response to adenovirus-mediated gene therapy Gene Therapy 1996 3: 154–162
Mastrangeli A et al. ‘Sero-switch’ adenovirus-mediated in vivo gene transfer: circumvention of anti-adenovirus humoral immune defenses against repeat adenovirus vector administration by changing the adenovirus serotype Hum Gene Ther 1996 7: 79–87
Mack CA et al. Circumvention of anti-adenovirus neutralizing immunity by administration of an adenoviral vector of an alternate serotype Hum Gene Ther 1997 8: 99–109
Ilan Y et al. Insertion of the adenoviral E3 region into a recombinant viral vector prevents antiviral humoral and cellular immune responses and permits long-term gene expression Proc Natl Acad Sci USA 1997 94: 2587–2592
Benihoud K et al. Efficient, repeated adenovirus-mediated gene transfer in mice lacking both tumor necrosis factor alpha and lymphotoxin alpha J Virol 1998 72: 9514–9525
Chirmule N et al. Role of E4 in eliciting CD4 T-cell and B-cell responses to adenovirus vectors delivered to murine and nonhuman primate lungs J Virol 1998 7: 6138–6145
Setoguchi Y, Jaffe HA, Chu CS, Crystal RG . Intraperitoneal in vivo gene therapy to deliver alpha 1-antitrypsin to the systemic circulation Am J Respir Cell Mol Biol 1994 10: 369–377
Smith TA et al. Transient immunosuppression permits successful repetitive intravenous administration of an adenovirus vector Gene Therapy 1996 3: 496–502
Yei S et al. Adenovirus-mediated gene transfer to cystic fibrosis: quantitative evaluation of repeated in vivo vector administration to the lung Gene Therapy 1994 1: 192–200
Van Ginkel FW et al. Intratracheal gene delivery with adenoviral vector induces elevated systemic IgG and mucosal IgA antibodies to adenovirus and beta-galactosidase Hum Gene Ther 1995 6: 895–903
Gahery-Segard H et al. Humoral immune response to the capsid components of recombinant adenoviruses: routes of immunization modulate virus-induced Ig subclass shifts Eur J Immunol 1997 27: 653–659
Bennett J, Pakola S, Zeng Y, Maguire A . Humoral response after administration of E1-deleted adenoviruses: immune privilege of the subretinal space Hum Gene Ther 1996 7: 1763–1769
Green DR, Ware CF . Fas-ligand: privilege and peril Proc Natl Acad Sci USA 1997 94: 5986–5990
Bramson JL, Hitt M, Gauldie J, Graham FL . Pre-existing immunity to adenovirus does not prevent tumor regression following intratumoral administration of a vector expressing IL-12but inhibits virus dissemination Gene Therapy 1997 4: 1069–1076
Li Z et al. Efficacy of multiple administrations of a recombinant adenovirus expressing wild-type p53 in an immune-competent mouse tumor model Gene Therapy 1998 5: 605–613
Li JJ et al. Percutaneous transluminal gene transfer into canine myocardium in vivo by replication-defective adenovirus Cardiovasc Res 1995 30: 97–105
Ueno H et al. Quantitative analysis of repeat adenovirus-mediated gene transfer into injured canine femoral arteries Arterioscler Thromb Vasc Biol 1995 15: 2246–2253
Schulick AH et al. Established immunity precludes adenovirus-mediated gene transfer in rat carotid arteries. Potential for immunosuppression and vector engineering to overcome barriers of immunity J Clin Invest 1997 99: 209–219
Mack CA et al. Salvage angiogenesis induced by adenovirus-mediated gene transfer of vascular endothelial growth factor protects against ischemic vascular occlusion J Vasc Surg 1998 27: 699–709
Rivard A et al. Rescue of diabetes-related impairment of angiogenesis by intramuscular gene therapy with adeno-VEGF Am J Pathol 1999 154: 355–363
Mack CA et al. Biologic bypass with the use of adenovirus-mediated gene transfer of the complementary deoxyribonucleic acid for vascular endothelial growth factor 121 improves myocardial perfusion and function in the ischemic porcine heart J Thorac Cardiovasc Surg 1998 115: 168–176; discussion 76–77
Giordano FJ et al. Intracoronary gene transfer of fibroblast growth factor-5 increases blood flow and contractile function in an ischemic region of the heart (see comments) Nature Med 1996 2: 534–539
Arai H, Gordon D, Nabel EG, Nabel GJ . Gene transfer of Fas ligand induces tumor regression in vivo Proc Natl Acad Sci USA 1997 94: 13862–13867
Larregina AT et al. FasL induces Fas/Apo1-mediated apoptosis in human embryonic kidney 293 cells routinely used to generate E1-deleted adenoviral vectors Gene Therapy 1998 5: 563–568
Chen P, Tian J, Kovesdi I, Bruder JT . Interaction of the adenovirus 14.7-kDa protein with FLICE inhibits Fas ligand-induced apoptosis J Biol Chem 1998 273: 5815–5820
Muruve DA et al. Adenovirus-mediated expression of Fas ligand induces hepatic apoptosis after Systemic administration and apoptosis of ex vivo-infected pancreatic islet allografts and isografts Hum Gene Ther 1997 8: 955–963
Piedra PA et al. Incidence and prevalence of neutralizing antibodies to the common adenoviruses in children with cystic fibrosis: implication for gene therapy with adenovirus vectors Pediatrics 1998 101: 1013–1019
Chinnadurai G, Chinnadurai S, Brusca J . Physical mapping of a large-plaque mutation of adenovirus type 2 J Virol 1979 32: 623–628
Graham FL, Smiley J, Russell WC, Nairu R . Characteristics of a human cell line transformed by DNA from human adenovirus type 5 J Gen Virol 1977 36: 59–77
Acknowledgements
We thank Jennifer Lee, Peter Genis and Emanuel Haney Jr for support with animal surgery, vector administration and animal care, Alena Lizonova, Angela Appiah and Lu Qin for their support with virus production and cell culture and Lisa DeBruyne, He Wang, Joan Keiser, David Gordon, Rob Panek, Mike Flynn, Doug Brough, Tom Wickham and Paul Fischer for insightful discussions. We also thank Rena Cohen and Kelly Raygor for preparation of the manuscript.
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Chen, P., Kovesdi, I. & Bruder, J. Effective repeat administration with adenovirus vectors to the muscle. Gene Ther 7, 587–595 (2000). https://doi.org/10.1038/sj.gt.3301137
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DOI: https://doi.org/10.1038/sj.gt.3301137
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