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Episomal vectors as gene delivery systems for therapeutic application

Objective

Many chronic human diseases cause great suffering as a result of inherited and sporadic genetic mutations. Gene therapy provides therapeutic benefit if a normal copy of the affected gene can be expressed in appropriate target cells. Retroviruses are often used for gene delivery, as the therapeutic gene integrates into a host cell chromosome. As integration is targeted to active chromatin this ensures long-term expression. However, this can disrupt gene expression at the integration site and lead to cancer. We propose that safe DNA vectors for human gene therapy must deliver therapeutic levels of gene expression without altering patterns of expression in the host cells. Extra-chromosomal gene expression vectors provide the best way of achieving this. Results will provide novel DNA vectors and protocols that will be used as gene delivery systems for therapeutic application. Expression vectors will be developed using rational design parameters that incorporate existing knowledge of genetic and epigenetic factors that regulate chromatin function in mammalian cells. DNA vectors will be designed specifically for ectopie gene expression from extra-chromosomal loci in the host cells, to provide regulated gene expression for safe, efficient and sustained gene therapy. Extra-chromosomal gene expression vectors will be validated for human gene therapy in a pre-clinical setting and protocols for clinical application established. Prototype extra-chromosomal gene expression systems that provide efficient and sustained gene expression will be refined to develop second-generation gene therapy vectors. We will use a systematic analysis of genetic elements to define design parameters for rational vector construction. The performance of second-generation gene expression vectors will be validated for human gene therapy in a pre-clinical setting and protocols for clinical application will be established using myocytes, hepatocytes and haemotopoeitic stems cells as model systems.

Field of science

  • /natural sciences/biological sciences/genetics and heredity/dna
  • /natural sciences/biological sciences/genetics and heredity/chromosome
  • /natural sciences/biological sciences/genetics and heredity/mutation
  • /medical and health sciences/medical biotechnology/genetic engineering/gene therapy

Call for proposal

FP6-2003-LIFESCIHEALTH-I
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Funding Scheme

STREP - Specific Targeted Research Project

Coordinator

THE UNIVERSITY OF MANCHESTER
Address
Oxford Road
Manchester
United Kingdom

Participants (7)

UNIVERSITEIT VAN AMSTERDAM
Netherlands
Address
Spui 21
Amsterdam
UNIVERSITY OF WITTEN / HERDECKE GGMBH
Germany
Address
Stockumer Strasse 10
Witten
ROYAL HOLLOWAY & BEDFORD NEW COLLEGE - UNIVERSITY OF LONDON
United Kingdom
Address
Egham Hill
Egham, Surrey
CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS
Spain
Address
Serrano, 117
Madrid
HELHOLTZ-ZENTRUM FUER INFEKTIONSFORSCHUNG GMBH
Germany
Address
Inhoffenstrabe 7
Braunschweig
THE HEBREW UNIVERSITY OF JERUSALEM
Israel
Address
The Authority For Research And Development, Edmond J. Safra Campus, Givat Ram
Jerusalem
GENOWAY SA
France
Address
181 Avenue Jean Jaurès
Lyon