Most 1st and 2nd generation Ad vectors have the transforming genes of Ad, E1A, and E1B intentionally deleted. In addition to their transformation functions, these genes play a major role in the complex co-evolution of the host immune response to adenovirus (Ad) infection and the adenovirus response to the host defense mechanisms. Moreover, most Ad vectors lack E3 genes that encode the 10.4 and 14.5K proteins (RID) that facilitate Fas degradation and a number of proteins that antagonize TNF function. In the absence of these genes, the most important viral immunosuppression pathways may have been eliminated. Based on our previous studies identifying TNF-alpha and, to a lesser, Fas as central functional elements in both the cellular and humoral systemic immune response to viral infection, and studies demonstrating that Ad E3 expression prolongs transgene expression and therapeutic effect, we propose the following: (1) To determine whether neutralization of TNF-alpha, Fas, interferons or combinations of these host defense pathways prolong Ad transgene expression in the lung and other sites and to determine the mechanisms whereby this occurs; (2) distinguish between the immune response to Ad alone, versus Ad expressing either self or foreign transgenes; (3) To identify other cytokines/chemokines that are part of the innate immune response to Ad transgenes; and (4) To achieve high expression of transgene product repetitively and in the face of an already existing immune response. If successful, these strategies should prove useful for gene therapy for cystic fibrosis in the future.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL051746-07
Application #
6318391
Study Section
Project Start
2000-06-01
Project End
2001-03-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
7
Fiscal Year
2000
Total Cost
$252,599
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Type
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
Ryan, Dorothy M; Vincent, Thomas L; Salit, Jacqueline et al. (2014) Smoking dysregulates the human airway basal cell transcriptome at COPD risk locus 19q13.2. PLoS One 9:e88051
Dvorak, Anna; Tilley, Ann E; Shaykhiev, Renat et al. (2011) Do airway epithelium air-liquid cultures represent the in vivo airway epithelium transcriptome? Am J Respir Cell Mol Biol 44:465-73
Krause, Anja; Whu, Wen Zhu; Xu, Yaqin et al. (2011) Protective anti-Pseudomonas aeruginosa humoral and cellular mucosal immunity by AdC7-mediated expression of the P. aeruginosa protein OprF. Vaccine 29:2131-9
Limberis, Maria P; Bell, Christie L; Heath, Jack et al. (2010) Activation of transgene-specific T cells following lentivirus-mediated gene delivery to mouse lung. Mol Ther 18:143-50
Song, Yuhu; Lou, Howard H; Boyer, Julie L et al. (2009) Functional cystic fibrosis transmembrane conductance regulator expression in cystic fibrosis airway epithelial cells by AAV6.2-mediated segmental trans-splicing. Hum Gene Ther 20:267-81
Vandenberghe, L H; Breous, E; Nam, H-J et al. (2009) Naturally occurring singleton residues in AAV capsid impact vector performance and illustrate structural constraints. Gene Ther 16:1416-28
Fein, David E; Limberis, Maria P; Maloney, Sean F et al. (2009) Cationic lipid formulations alter the in vivo tropism of AAV2/9 vector in lung. Mol Ther 17:2078-87
Limberis, Maria P; Vandenberghe, Luk H; Zhang, Liqun et al. (2009) Transduction efficiencies of novel AAV vectors in mouse airway epithelium in vivo and human ciliated airway epithelium in vitro. Mol Ther 17:294-301
Tertilt, Christine; Joh, Ju; Krause, Anja et al. (2009) Expression of B-cell activating factor enhances protective immunity of a vaccine against Pseudomonas aeruginosa. Infect Immun 77:3044-55
Limberis, M P; Bell, C L; Wilson, J M (2009) Identification of the murine firefly luciferase-specific CD8 T-cell epitopes. Gene Ther 16:441-7

Showing the most recent 10 out of 85 publications