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New systems of controlled gene expression for improved delivery of therapeutic substances

   
Project

QLK3-2000-00721

Cell factory area

3.1.2

EU Contribution

1 383 841 Euro

Duration

36 months

Type

Research project

Starting date

01-03-2001

Keywords
anti-angiogenic agents
cytokines
gene tranfer systems
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ABSTRACT
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This proposal wishes to contribute to the development of new treatments against the high frequency diseases of cancer, retinopathies and atherosclerosis, touching up to 42% of the population. The proposed approach is to create new gene transfer systems based on programmes of coupled transcriptional and post-transcriptional regulations of gene expression, for an efficient and controlled delivery of active therapeutic agents. Regulatory tools emerging from fundamental research results will allow the creation of new vectors and of genetically modified cells efficiently expressing combinations of anti-angiogenic agents or growth factors and cytokines. Anti-angiogenesis can target up to 100% of solid tumours and most retinopathies. Angiogenic and anti-inflammatory agents target atheroma plaque, to prevent myocardial infarction.

The vectors and cell lines delivering therapeutic substances, tested on animals models, will be commercialised to big industrial companies in Europe that think launching clinical assays and exploit them in a large scale. This programme is expected to create a large added value for European community.

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OBJECTIVES
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The objective of this project is to contribute to the quality of life and health improvement by developing new systems for the delivery of therapeutic substances targeting high frequency and/or severity diseases. This proposal involves four European countries and extends from fundamental research to pre-clinical application and commercialisation.

The originality of the concepts underpinning this present RTD proposal is to combine the major aspects of gene regulation to develop viable expression tools for therapeutic applications: mRNA transcription, stability and translation. New vectors and genetically modified cells will be created and characterised for efficient delivery of new combinations of therapeutic substances (anti-angiogenic agents, growth factors and cytokines) to target diseases related to the vascular system: cancers (anti-angiogenic approach can target 100% of solid tumours), retinopathies, and atherosclerosis, touching up to 42% of the industrialised countries population.

These novel deliverables will be commercialised by the two SMEs of the consortium to big industrial companies which will exploit them in clinical assays.

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DESCRIPTION OF WORK
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The research and development work is divided into nine workpackages.

Novel expression tools will be generated in WP1 to 4. WP1 will develop novel transcriptional regulation systems. WP2 and WP3 are devoted to the development of translational enhancers:

  • New hyperactive and tissue specific IRESes, RNA enhancers capable of allowing the expression of several proteins from a single mRNA in a correct stoechiometry.
  • Translational regulatable RNA elements, involving the use of transactivators or -silencers.

Combined transcription-translation regulatory systems will be created. WP4 is the development of an mRNA destabilising system.

The new expression tools will lead to the generation of viral and non-viral vectors, in WP5, whose original feature is to be multicistronic, able to co-express up to five proteins. Vectors will be constructed containing, in addition, the transcriptional inducible system or the coupled regulation of transcription and transcript stability. These vectors will first be tested with reporter genes, then used for the transfer of genes expressing therapeutic substances.

WP6 will generate genetically modified cells and tissues. Cells will be reprogrammemed to express trans-activators or -silencers to provide technological tools for improved regulatable protein expression (induction in response to a drug). Modified cell lines will also be generated to express therapeutic molecules, which are angiogenic, anti-angiogenic and anti-inflammatory agents.

WP7 will exploit WP5 and WP6 (multicistronic concept) to deliver therapeutic substances in vivo. Co-expression of a cocktail of anti-angiogenic factors (inhibitors of blood vessels formation) will be assessed for blocking tumour progression and metastatic propagation and to inhibit abnormal retinal neoangiogenesis in WP7. Combinations of growth factors and cytokines will be characterised for their ability to prevent atheroma plaque destabilisation and myocardial infarction.

WP8 will commercialise the deliverables to big European companies developing gene therapy programmes against cancer and cardiovascular diseases. Contracts will be established with these companies that have the ability to perform the clinical assays and to diffuse the therapeutic substances on a large scale.

WP9 is consortium administration and management of results.

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DELIVERABLES
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  • Preferment novel expression tools (WP1 to 4) available from m6 to 18 (depending on the DL).
  • New vectors available from m12 to 24 (depending on vector families).
  • Modified cells expected from m12 (scaled from m12 to 30).
  • Delivery of therapeutic substances in vivo: as soon as results obtained in vivo (expected from m18 to m36) are demonstrated as reliable, (80 to 100% efficiency expected), assays will be conducted on a bigger scale to prepare efficient cocktails of active therapeutic substances.
  • Commercialisation to big companies: from m18 to 36.

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CONSORTIUM
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  INSERM (France)
Partner 1 involves personnel from:
INSERM U397 (director: Pr Francis Bayard) in Toulouse
Endocrinologie et Communication Cellulaire
Institut Fédératif de Recherche Louis Bugnard
CHU Rangueil, Bat. L3, 1 avenue Jean Poulhes
31403 Toulouse Cedex 4, France
Tel: +33 561322142 or +33 561322811 (secrétariat)
Fax: +33 561322141
pratsac@rangueil.inserm.fr

The project involves three complementary staffs of INSERM U397 directed by
1. Dr. Jean-François Arnal (pathophysiology, atherosclerosis)

2. Dr. Anne-Catherine Prats (molecular biology, vectorology)
3. Prof. Hervé Prats (molecular biology, angiogenesis and anti-angiogenesis)

INSERM U386 (director: Dr. Jean-Jacques Toulmé) in Bordeaux
Université Victor Segalen
146 rue Léo Saignat
33076 Bordeaux, France
57571014 (secrétariat) or +33 557571017 (direct)

Fax: +33 557571015
Jean-Jacques.Toulme@bordeaux.inserm.fr

The project manager is Dr. Anne-Catherine Prats
P1 is responsible for WP7, WP8 and WP9

Cistronics Cell Technology GmbH (SME) in Zürich (Martin Fussenegger)
Responsible for WP1 and WP6
Cistronics is a spin-off company of the Swiss Federal Institute of Technology (the ETH) Cistronics Cell Technology GmbH
Einsteinstraße 1-5
PO Box 145
8093 Zürich, Switzerland
Tel: +41 793369500
Fax: +41 790863369500
fussenegger@biotech.biol.ethz.ch

University of Cambridge, Cambridge Richard J. Jackson)
Responsible for WP2
University of Cambridge
Dpt of Biochemistry
80, Tennis Court Road
CB2 1GA Cambridge, United Kingdom
Tel: +44 1223332265
Fax: +44 1223332988
rjj@mole.bio.cam.ac.uk

Université Libre de Bruxelles (Georges Huez and Véronique Kruys)
Responsible for WP3
Laboratoire de Chimie Biologique
IBMM Université Libre de Bruxelles
12 rue des Profs Jeener et Brachet
6041 Gosselies, Belgium
Tel: +32 26509804
Fax: +32 26509800
ghuez@ulb.ac.be
or vkruys@dbm.ulb.ac.be

CNRS UPR 41, Rennes (H. Beverley Osborne)
Responsible for WP4
Université de Rennes 1
Faculté de Médecine
2 av. Pr. Leon Bernard,
CS 34317,
35043 Rennes Cedex, France
Tel: +33 299336276
Fax: +33 299336200
beverley.osborne@univ-rennes1.fr

MILLEGEN Sarl, Ramonville (H. Kharrat)
Responsible for WP5
Dpt de Thérapie Génique
10, Avenue de l'Europe
31525 Ramonville St Agne, France
Tel: +33 561285638
Fax: +33 561285600
millegen@wanadoo.fr

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