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Prevention of Small Diameter Prosthetic Vascular Graft Failure by Ex-Vivo Gene Therapy with Infected Fibroblasts and/or Biologically Active Peptides

Objective

The objective of this proposal is to identify new strategies to improve the patency rate of small diameter (< 4mm) prosthetic vascular grafts (SDPVG) following arterial reconstruction. More specifically, in this proposal it is planned to examine whether new ex-vivo gene therapy strategies with replication deficient adenovirus vectors and/or the use of biologically active peptides (BAPs) can reduce graft failure rate by achieving the following effects: a) reduction of SDPVG surface thrombogenicity, b) inhibition of SMCs proliferation on the luminal surface of the graft, c) inhibition of SMCs and fibroblasts migration from the surrounding tissues into the mesh of the graft.

We plan to use 4mm internal diameter knitted Dacron grafts processed as follows:

1) graft coating with fibroblasts infected with Ad-vector carrying the cDNA for Tissue Inhibitor of Metalloproteinase 1 (TIMP-1) to prevent SMC migration into the graft.
2) graft coating with fibroblasts infected with Ad-vector carrying the cDNA for Tissue Inhibitor of Metalloproteinase 2 (TIMP-2) to prevent SMC migration into the graft.
3) graft coating with fibroblasts infected with Ad-vector carrying the cDNA for Insulin-like Growth Factor type 1 soluble receptor (IGF- 1 Rsol) to prevent SMC proliferation into the graft.
4) graft coating with fibroblasts infected with Ad-vector carrying the cDNA for Tissue Plasminogen Activator (t-PA) to induce local fibrinolysis.
5) graft coating with a BAP antagonist to Platelet integrin Glycoprotein IIb/IIIa receptor:
6) graft coating with a BAP from the RGD-family peptides to prevent platelet aggregation to the graft.
7) graft coating with a BAP related to Collagenase IV to prevent SMC migration
8) graft coating with a BAP antagonist to basic Fibroblast Growth Factor (bFGF) to prevent SMC proliferation into the graft.

These grafts will first be tested in vitro both under static and dynamic conditions. The most promising grafts (2 covered with BAPs and 2 with Ad-vectors) will then be tested in-vivo in the pig carotid artery model.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

Istituto Dermopatico dell'Immacolata
Address
Via Dei Monti Di Creta 104
00167 Roma
Italy

Participants (3)

ANGIOLOGICA B.M. SRL
Italy
Address
Via Giovanni Xxiii 7
27028 San Martino Siccomario
The Victoria University of Manchester
UNIVERSITY OF ALCALA
Spain
Address
33,6,Ctra N-ii 33,6 Campus Universitario
28871 Alcala De Henares