Gene therapy of vascular endothelium to combat diseases of, or controlled by, the vascular system

Información del proyecto

Identificador del acuerdo de subvención: IC20980206

Proyecto cerrado

Fecha de inicio 1 Mayo 1998

Fecha de finalización 30 Abril 2001

Financiado con arreglo a

• Specific research, technological development and demonstration programme in the field of cooperation with third countries and international organizations, 1994-1998

Coste total

Sin datos

Aportación de la UE

Sin datos

Coordinado por

UNIVERSITY OF VIENNA
Austria

Objetivo

The objectives of the proposed study include:
1- To develop adenoviral and other vectors to direct endothelial cell specific, long term expression
2- To
test strategies to prevent vascular cell activation in inflammation and atherosclerosis
3- To create an endothelial cell layer which interferes with the action of T cells in allotransplants
4- To design novel strategies to block
tumor angiogenesis
5- To direct synthesis of peptides to the brain in models of stroke and degenerative brain diseases
Brief description:
Vascular endothelium
forms a biological interface between circulating blood elements and the subendothelial cells and controls the exchange of substances, peptides and immune cells between the blood stream and all the various tissues of the body. The single-cell thick endothelial cell membrane is a multifunctional organ which is essential to normal vascular physiology and homeostasis. Endothelial dysfunction can be triggered by infectious agents and an imbalanced activation of the immune system, which leads to inflammation, coagulation and changes in blood flow due to vessel obstruction. Overproliferation of vascular cells is associated with restenosis and atherosclerosis and the induction of capillary growth is a prerequesite for the growth of solid tumors. Due to its accessibility from the blood stream and its intimate relationship to all tissues of the body the endothelium is a candidate organ to test, by the use of genetic methods, strategies
i) to prevent a series of vascular dysfunctions and
ii) to direct production of peptides to certain organs such as the brain.
This project proposes to generate novel viral vectors to direct transgene expression to the endothelium and to achieve long term transgene expression. We have available from our previous work recombinant adenoviruses expressing the natural inhibitor of the transcription factor NFkappaB, IkappaB, several inhibi cytokines and the apoptosis inducing Fas ligand. The obtained results demonstrate that activation of endothelial cells is blocked by IhB leading to a complete inhibition of cytokine production, immune cell adhesion and clotting induction. Further, ectopic expression of the Fas ligand functions to induce apoptosis of alloreactive T cells. We propose now to use endothelial cells infected with adenovirus-lkappaB constructs in several disease models where endothelial cell activation is playing a major role and to test adenovirus-Fas-ligand constructs in transplantation of solid organs to prevent graft rejection. We will further test strategies to inhibit tumor angiogenesis and to direct expression of peptides to the brain. To achieve these goals eight complementary laboratories will collaborate: One group has generated the Ikappa expressing adenoviral vectors (U. Wien), a second group several adenoviruses expressing inhibitive cytokines (INSERM/Transplant), while another has generated a variety of vectors expressing the Fas ligand (U. Manchester). These laboratories have experience in the construction of DNA viral vectors, will work on improved expression of relevant regulatory proteins and deliver viruses to the other groups. A fourth group has a long-standing experience in IL1-induced inflammation (MarioNegri/Immunol), another laboratory is specialized in allotransplant rejection (INSERM/Transplant). A fifth group is an expert in angiogenesis (MPI/CellBiol).
Two further laboratories in a clinical setting will contribute their experience in inflammatory brain diseases (U. Zürich) and stroke (U. Budapest). Finally, strategies in the context of atherosclerosis and Alzheimer disease will be explored (IMBB/Hellas).
This partnership provides a unique combination of complementary expertises in gene therapy and molecular medicine. We believe that the results will lead to improved treatments of highly prevalent human diseases in Europe like inflammations, artherosclerosis, transplant rejection, cancer, stroke and Alzheimer disease. As such it should contribute to the European competitiveness in the developing area of gene therapy of the vascular system.
Keywords: gene therapy, endothelium, inflammation, transplant, angiogenesis, atherosclerosis, Alzheimer

Ámbito científico (EuroSciVoc)

• ciencias médicas y de la salud › medicina básica › neurología › demencia › alzheimer
• ciencias médicas y de la salud › biotecnología médica › ingeniería genética › terapia génica
• ciencias médicas y de la salud › medicina clínica › cardiología › enfermedad cardiovascular › arteriosclerosis
• ciencias médicas y de la salud › medicina básica › inmunología
• ciencias médicas y de la salud › medicina básica › neurología › accidente cerebrovascular

Programa(s)

• FP4-INCO - Specific research, technological development and demonstration programme in the field of cooperation with third countries and international organizations, 1994-1998

Tema(s)

Datos no disponibles

Convocatoria de propuestas

Datos no disponibles

Régimen de financiación

CSC - Cost-sharing contracts

Coordinador

UNIVERSITY OF VIENNA

• Aportación de la UE: Sin datos
• Dirección: 59,Brunnerstrasse 59 ; 1235 WIEN ; Austria
• Coste total: Sin datos

Participantes (1)

National Institute of Psychiatry and Neurology, National Stroke Center

Hungría

• Aportación de la UE: Sin datos
• Dirección: 116,Huvösvölgyi Ut. ; 1021 Budapest
• Coste total: Sin datos