Periocular triamcinolone enhances intraocular gene expression after delivery by adenovirus.

PURPOSE A noninvasive imaging technique was used for serial assessment of gene expression after intraocular gene transfer. Bioluminescence after intravitreous administration of an adenovirus vector containing the firefly luciferase gene was measured serially and noninvasively. The optical signal was then used as a bioassay to determine whether periocular immune modulation affects intraocular transgene expression. METHODS Sixty-two, 8-week-old, male BALB/c mice were used. The correlation of optical signal intensity was determined by tissue luciferase level after injecting 30 mice with one of three intravitreous doses of Ad-Luc-GFP (10(8), 5 x 10(8), or 10(9) particles in 1 microL). Ocular bioluminescence was measured at days 2, 5, 8, and 14. The bioluminescence was then directly compared with measured tissue luciferase levels. The remaining 32 mice were divided into two groups. One group (n = 16), was injected with periocular corticosteroid (400 mug in 10 microL). Two days later, Ad-Luc-GFP was administered by intravitreous injection (10(9) particles in 1 microL). The remaining mice (n = 16) were injected with the same dose of intravitreous Ad-Luc-GFP without corticosteroid pretreatment. Ocular bioluminescence was then assessed longitudinally on days 2, 4, 6, 8, 11, 14, 22, and 30 after intravitreous injection in n = 10 mice per group. The optical signal intensity in each group was compared over the study period. The remaining 12 mice (n = 6, each group) were used to assess histologic differences between the two groups. RESULTS In vivo measurement of ocular bioluminescence was well correlated with tissue luciferase levels (Spearman's correlation, r = 0.969, P < 0.001). Periocular TA injection markedly decreased the acute inflammatory reaction associated with intravitreous Ad-Luc-GFP and was associated with a significant increase in the duration of peak luciferase expression as well as the total period of luciferase expression. CONCLUSIONS A significant enhancement of intraocular transgene expression is associated with periocular pretreatment with corticosteroid. Histologic evidence of immune cell reduction in ocular tissues in corticosteroid-treated eyes implies a local immune response. Periocular treatment with corticosteroids may enhance adenovirus-mediated gene expression in the eye.

[1]  J. Garcia-Arumi,et al.  Photodynamic therapy with intravitreal triamcinolone in predominantly classic choroidal neovascularization: one-year results of a randomized study. , 2006, Ophthalmology.

[2]  Philip J Rosenfeld,et al.  Ranibizumab for neovascular age-related macular degeneration. , 2006, The New England journal of medicine.

[3]  R. Avery,et al.  Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy. , 2006, Ophthalmology.

[4]  J. Simpson,et al.  Intravitreal triamcinolone for refractory diabetic macular edema: two-year results of a double-masked, placebo-controlled, randomized clinical trial. , 2006, Ophthalmology.

[5]  R. Ali,et al.  Gene therapy progress and prospects: the eye , 2006, Gene Therapy.

[6]  J. Jonas.  Intravitreal Triamcinolone Acetonide: A Change in a Paradigm , 2006, Ophthalmic Research.

[7]  Christopher H. Contag,et al.  In vivo imaging using bioluminescence: a tool for probing graft-versus-host disease , 2006, Nature Reviews Immunology.

[8]  P. Barnes.  Corticosteroids: the drugs to beat. , 2006, European journal of pharmacology.

[9]  M. Bureau,et al.  Optical imaging of luminescence for in vivo quantification of gene electrotransfer in mouse muscle and knee , 2006, BMC biotechnology.

[10]  P. Campochiaro,et al.  Adenoviral vector-delivered pigment epithelium-derived factor for neovascular age-related macular degeneration: results of a phase I clinical trial. , 2006, Human gene therapy.

[11]  D. Guyer,et al.  Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease , 2006, Nature Reviews Drug Discovery.

[12]  W. Mieler,et al.  Response of retinoblastoma with vitreous tumor seeding to adenovirus-mediated delivery of thymidine kinase followed by ganciclovir. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  M. Chillón,et al.  Gutless adenovirus: last-generation adenovirus for gene therapy , 2005, Gene Therapy.

[14]  N. Lemoine,et al.  Herpesvirus saimiri-based vector biodistribution using noninvasive optical imaging , 2005, Gene Therapy.

[15]  S. Diamond,et al.  Targeting viral-mediated transduction to the lung airway epithelium with the anti-inflammatory cationic lipid dexamethasone-spermine. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[16]  R. Mandel,et al.  Recombinant adeno-associated viral vectors in the nervous system. , 2005, Human gene therapy.

[17]  M. Weitzman,et al.  Gene therapy: twenty-first century medicine. , 2005, Annual review of biochemistry.

[18]  D. Vollrath,et al.  phiC31 integrase confers genomic integration and long-term transgene expression in rat retina. , 2005, Investigative ophthalmology & visual science.

[19]  J. Bergelson,et al.  CAR: a virus receptor within the tight junction. , 2005, Advanced drug delivery reviews.

[20]  Y. Péréon,et al.  Postsurgical assessment and long-term safety of recombinant adeno-associated virus-mediated gene transfer into the retinas of dogs and primates. , 2005, Archives of ophthalmology.

[21]  S. Lightman,et al.  ORIGINAL ARTICLE Combined Orbital Floor Betamethasone and Depot Methylprednisolone in Uveitis , 2005, Ocular immunology and inflammation.

[22]  B. Klaunberg,et al.  In vivo bioluminescence imaging. , 2004, Comparative medicine.

[23]  P. Chévez-Barrios,et al.  Efficient gene transfer into retinal cells using adenoviral vectors: dependence on receptor expression. , 2004, Investigative ophthalmology & visual science.

[24]  J. Edelman,et al.  Corticosteroids inhibit VEGF-induced vascular leakage in a rabbit model of blood-retinal and blood-aqueous barrier breakdown. , 2004, Experimental eye research.

[25]  Z. Paroo,et al.  Validating bioluminescence imaging as a high-throughput, quantitative modality for assessing tumor burden. , 2004, Molecular imaging.

[26]  A. El-Aneed,et al.  An overview of current delivery systems in cancer gene therapy. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[27]  Cameron S. Osborne,et al.  LMO2-Associated Clonal T Cell Proliferation in Two Patients after Gene Therapy for SCID-X1 , 2003, Science.

[28]  J. Gu,et al.  Enhancing adenovirus‐mediated gene transfer in vitro and in vivo by addition of protamine and hydrocortisone , 2003, The journal of gene medicine.

[29]  S. Y. Lee,et al.  Cell uptake and tissue distribution of radioiodine labelled D-luciferin: implications for luciferase based gene imaging , 2003, Nuclear medicine communications.

[30]  M. Kay,et al.  Looking into the safety of AAV vectors , 2003, Nature.

[31]  David S. Reay,et al.  Virtual solution to carbon cost of conferences , 2003, Nature.

[32]  J. Bennett.  Immune response following intraocular delivery of recombinant viral vectors , 2003, Gene Therapy.

[33]  S S Gambhir,et al.  Optical imaging of transferrin targeted PEI/DNA complexes in living subjects , 2003, Gene Therapy.

[34]  P. Campochiaro,et al.  Periocular injection of an adenoviral vector encoding pigment epithelium-derived factor inhibits choroidal neovascularization , 2003, Gene Therapy.

[35]  S. Gambhir,et al.  Molecular imaging in living subjects: seeing fundamental biological processes in a new light. , 2003, Genes & development.

[36]  I. Runnebaum,et al.  CAR is a cell–cell adhesion protein in human cancer cells and is expressionally modulated by dexamethasone, TNFα, and TGFβ , 2003, Gene Therapy.

[37]  M. Naud,et al.  Inhibition of experimental autoimmune uveoretinitis by systemic and subconjunctival adenovirus‐mediated transfer of the viral IL‐10 gene , 2002, Clinical and experimental immunology.

[38]  P. Campochiaro,et al.  Regression of ocular neovascularization in response to increased expression of pigment epithelium-derived factor. , 2002, Investigative ophthalmology & visual science.

[39]  Peter Gehlbach,et al.  Intraocular adenoviral vector-mediated gene transfer in proliferative retinopathies. , 2002, Investigative ophthalmology & visual science.

[40]  J. Bennett,et al.  A deviant immune response to viral proteins and transgene product is generated on subretinal administration of adenovirus and adeno-associated virus. , 2002, Molecular therapy : the journal of the American Society of Gene Therapy.

[41]  P. Campochiaro,et al.  Clinical protocol. An open-label, phase I, single administration, dose-escalation study of ADGVPEDF.11D (ADPEDF) in neovascular age-related macular degeneration (AMD). , 2001, Human gene therapy.

[42]  P. Kaufman,et al.  Non‐invasive observation of repeated adenoviral GFP gene delivery to the anterior segment of the monkey eye in vivo , 2001, The journal of gene medicine.

[43]  R. Hurwitz,et al.  Immune consequences of intraocular administration of modified adenoviral vectors. , 2001, Human gene therapy.

[44]  J. Bennett,et al.  Additional transduction events after subretinal readministration of recombinant adeno-associated virus. , 2000, Human gene therapy.

[45]  K. Schughart,et al.  In vitro and in vivo effects of glucocorticoids on gene transfer to skeletal muscle , 1999, FEBS letters.

[46]  D. Hunt,et al.  Immune responses limit adenovirally mediated gene expression in the adult mouse eye , 1998, Gene Therapy.

[47]  C. Caskey,et al.  An adenoviral vector deleted for all viral coding sequences results in enhanced safety and extended expression of a leptin transgene. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[48]  V. Sandig,et al.  Reactivation of the Previously Silenced Cytomegalovirus Major Immediate-Early Promoter in the Mouse Liver: Involvement of NFκB , 1998, Journal of Virology.

[49]  J. Bennett,et al.  Cell-mediated immune response and stability of intraocular transgene expression after adenovirus-mediated delivery. , 1997, Investigative ophthalmology & visual science.

[50]  R. Fiscella,et al.  Intraocular penetration of periocular ketorolac and efficacy in experimental uveitis. , 1996, Investigative ophthalmology & visual science.

[51]  J. Bennett,et al.  In vivo gene transfer into murine corneal endothelial and trabecular meshwork cells. , 1995, Investigative ophthalmology & visual science.

[52]  Jean Bennett,et al.  Adenovirus vector-mediated in vivo gene transfer into adult murine retina. , 1994, Investigative ophthalmology & visual science.

[53]  B. A. Forbes,et al.  The effects of a promoter of cell differentiation and selected hormones on human cytomegalovirus infection using an in vitro cell system. , 1990, The Journal of infectious diseases.

[54]  J. Streilein,et al.  Anterior chamber associated immune deviation: the privilege of immunity in the eye. , 1990, Survey of ophthalmology.

[55]  D. Brough,et al.  Repeated administration of adenovector in the eye results in efficient gene delivery. , 2006, Investigative ophthalmology & visual science.

[56]  James M. Wilson.  Adeno-associated virus and lentivirus pseudotypes for lung-directed gene therapy. , 2004, Proceedings of the American Thoracic Society.

[57]  G. Nemerow,et al.  In vivo transduction of photoreceptors or ciliary body by intravitreal injection of pseudotyped adenoviral vectors. , 2003, Molecular therapy : the journal of the American Society of Gene Therapy.

[58]  P. Lowenstein,et al.  Acute direct adenoviral vector cytotoxicity and chronic, but not acute, inflammatory responses correlate with decreased vector-mediated transgene expression in the brain. , 2001, Molecular therapy : the journal of the American Society of Gene Therapy.