The overall goal of this Program Project is to develop improved vectors for gene delivery in vivo and the application of these vectors for treatment of cardiovascular disease in experimental animals. There are four research projects supported by four core units and complemented by two pilot and feasibility projects. The objective of Project l is to develop and test gutless adenoviral vectors using reporter genes, and to test of the utility of these vectors in the in vivo delivery of the low density lipoprotein receptor (LDLR) and the very low density lipoprotein receptor (VLDLR) genes in the treatment of hypercholesterolemia in experimental animals. In close collaboration with Project 2, helper- dependent adenoviral vectors will be produced and strategies will be developed to ensure long-term expression by transient immunosuppression, use of vectors of different serotypes, and use of gutless adenoviral vectors totally devoid of viral genes. Experimental animals will be normal mice, LDLR -/- mice and heterozygous LDLR-deficient rhesus monkeys. Project 2 will collaborate with Projects 1, 3, and 4 to develop gutless vectors for experiments in vitro and in vivo using helper-dependent viruses that contain viron protein genes from different serotypes. It will also develop integrating adenoviral vectors using a eukaryotic transposable element. Project 3 will apply a drug dependent regulatable system to produce transgenic mice that express LDLR that can be turned on by an exogenous ligand. It will optimize the system for possible use in humans in the future and to incorporate into helper-dependent gutless adenoviral vectors developed in Projects 1 and 2. Project 4 will test systematically the utility of adenoviral gene transfer to diminish the extent of apoptosis after coronary artery ligation, for five complementary classes of protein with proven ability to inhibit apoptosis in vitro. These projects will be supported by an Administrative Core, a Primate Core (at the Southwest Foundation for Biomedical Research where the rhesus monkeys are housed) which conducts the primate experiments ii collaboration with Projects 1, 2 and 3, and Vector Production Core, which produces large amounts of high quality gutless vectors for in vivo use. Two pilot and feasibility projects have been selected from eleven submissions for inclusion in this application. They deal with (i) control of antigen presentation in gene therapy and (ii) apoptosis-based gene therapy of vascular smooth muscle.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
1P50HL059314-01
Application #
2655301
Study Section
Special Emphasis Panel (ZHL1-CSR-B (S1))
Project Start
1997-09-30
Project End
2002-08-31
Budget Start
1997-09-30
Budget End
1998-08-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
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Palmer, Donna J; Ng, Philip (2011) Rescue, amplification, and large-scale production of helper-dependent adenoviral vectors. Cold Spring Harb Protoc 2011:857-66
Palmer, Donna J; Ng, Philip (2011) Characterization of helper-dependent adenoviral vectors. Cold Spring Harb Protoc 2011:867-70
Stephen, Sam Laurel; Montini, Eugenio; Sivanandam, Vijayshankar Ganesh et al. (2010) Chromosomal integration of adenoviral vector DNA in vivo. J Virol 84:9987-94
Sakai, Keiko; Tiebel, Oliver; Ljungberg, M Cecilia et al. (2009) A neuronal VLDLR variant lacking the third complement-type repeat exhibits high capacity binding of apoE containing lipoproteins. Brain Res 1276:11-21
Brunetti-Pierri, Nicola; Stapleton, Gary E; Law, Mark et al. (2009) Efficient, long-term hepatic gene transfer using clinically relevant HDAd doses by balloon occlusion catheter delivery in nonhuman primates. Mol Ther 17:327-33
Palmer, Donna J; Ng, Philip (2008) Methods for the production of helper-dependent adenoviral vectors. Methods Mol Biol 433:33-53
Palmer, Donna J; Ng, Philip (2008) Methods for the production of first generation adenoviral vectors. Methods Mol Biol 433:55-78
Brunetti-Pierri, Nicola; Stapleton, Gary E; Palmer, Donna J et al. (2007) Pseudo-hydrodynamic delivery of helper-dependent adenoviral vectors into non-human primates for liver-directed gene therapy. Mol Ther 15:732-40
Oka, K; Belalcazar, L M; Dieker, C et al. (2007) Sustained phenotypic correction in a mouse model of hypoalphalipoproteinemia with a helper-dependent adenovirus vector. Gene Ther 14:191-202

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