Abstract

Expandable metallic stents have been successfully utilized to relieve coronary arterial obstruction During this past year in the United States more then five hundred thousand coronary stents were used. Furthermore, there has been increasing interest in drug delivery stents to prevent restenosis following stent angioplasty. Our laboratory has pioneered the use of stents as platforms for gene delivery systems for arterial wall gene therapy. In this research program, we will address the following hypothesis: Gene therapy for in-stent restenosis and stabilization of vulnerable plaque can be achieved with a gene delivery stent. Our gene delivery stent utilizes antibody-mediated tethering of replication defective adenoviral gene vectors; this results in enhanced site specific ta'ansgene expression, and a highly localized biodistribution restricted to the site of stent deployment.
Aims Aim 1 : Polyaminobisphosphonate-steel interactions with subsequent polyamine and antibody binding: Formulation and Characterization. Bisphosphonate chemosorption will be the basis for a molecular surface modification of the steel stents either directly or with amplifying polyamines, to permit the covalent binding of anti-adenoviral antibodies to amino groups using bifunctional crosslinking, thereby enabling vector tethering.
Aim 2 : Formulation and characterization of the steel-PAABP-antibody gene delivery system: Ceil culture studies. Arterial smooth muscle cell cultures will be used as a model system to investigate the mechanism of gene delivery, fi-galactosidase (LacZ) and Green Fluorescent Protein (GFP) will be used as the reporter genes for these experiments.
Aim 3 : In vivo efficiency and anti-in-stent restenosis efficacy. Pig coronary stent studies will use the optimal formulations based on Aims 1 and 2. Reporter studies (LacZ) will focus on in vivo efficiency and biodistribution of vector. The therapeutic gene will be Fas-Ligand, a pro-apoptotic protein with established efficacy for restenosis. The chief therapeutic endpoint will be extent of inhibition of neointimal formation.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL072108-02
Application #
6696325
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Old, Susan E
Project Start
2003-02-01
Project End
2007-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
2
Fiscal Year
2004
Total Cost
$458,090
Indirect Cost

  Institution

Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Slee, Joshua B; Alferiev, Ivan S; Nagaswami, Chandrasekaran et al. (2016) Enhanced biocompatibility of CD47-functionalized vascular stents. Biomaterials 87:82-92
Fishbein, Ilia; Forbes, Scott P; Adamo, Richard F et al. (2014) Vascular gene transfer from metallic stent surfaces using adenoviral vectors tethered through hydrolysable cross-linkers. J Vis Exp :e51653
Fishbein, Ilia; Forbes, Scott P; Chorny, Michael et al. (2013) Adenoviral vector tethering to metal surfaces via hydrolyzable cross-linkers for the modulation of vector release and transduction. Biomaterials 34:6938-48
Fishbein, Ilia; Chorny, Michael; Adamo, Richard F et al. (2013) Endovascular Gene Delivery from a Stent Platform: Gene- Eluting Stents. Angiol Open Access 1:
Forbes, Scott P; Alferiev, Ivan S; Chorny, Michael et al. (2013) Modulation of NO and ROS production by AdiNOS transduced vascular cells through supplementation with L-Arg and BH4: implications for gene therapy of restenosis. Atherosclerosis 230:23-32
Chorny, Michael; Alferiev, Ivan S; Fishbein, Ilia et al. (2012) Formulation and in vitro characterization of composite biodegradable magnetic nanoparticles for magnetically guided cell delivery. Pharm Res 29:1232-41
Chorny, Michael; Fishbein, Ilia; Adamo, Richard F et al. (2012) Magnetically targeted delivery of therapeutic agents to injured blood vessels for prevention of in-stent restenosis. Methodist Debakey Cardiovasc J 8:23-7
Chorny, Michael; Hood, Elizabeth; Levy, Robert J et al. (2010) Endothelial delivery of antioxidant enzymes loaded into non-polymeric magnetic nanoparticles. J Control Release 146:144-51
Fishbein, Ilia; Chorny, Michael; Levy, Robert J (2010) Site-specific gene therapy for cardiovascular disease. Curr Opin Drug Discov Devel 13:203-13
Chorny, Michael; Levy, Robert J (2009) Site-specific analgesia with sustained release liposomes. Proc Natl Acad Sci U S A 106:6891-2

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