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Meganucleases for Gene Replacement

Objective

Genetic diseases can only be truly cured via restoration of defective gene function. Homologous recombination is the ultimate tool for gene replacement, but is limited by low efficiency and reproducibility. DNA double-strand breaks enhance the efficiency o f homologous recombination in vitro dramatically, however for in vivo applications absolute site-specificity is crucial.

Engineered, highly specific DNA endonucleases (meganucleases) with programmable specificity are the key to a wider use of homologous recombination in gene replacement. MenuG seeks to develop meganucleases that cleave only at positions of interest in a genomic context with the aim to solve - based on homologous recombination - the main problem in gene therapy: to replace genes efficiently, selectively and reproducibly.

Three types of meganucleases will be engineered:
- programmed restriction enzymes,
- novel or redesigned homing endonucleases,
- redesigned Type IIS restriction enzymes.

These will be tested for in vitro cleavage specificity, delivery into the nuclei, in vivo cleavage specificity and induction of double-strand break repair by homologous recombination. Promising meganucleases will be tested for gene replacement in Pompe metabolic disease.

Concepts for commercial applications will be developed. MenuG is a high-risk project, starting from the engineering of programmable meganucleases to efficient cell delivery and specific action on a defined genetic locus. It has a high impact profile with potentially enormous benefits primarily in the treatment of inherited monogenetic diseases, but in principle also of multigenic disorders, including cancer. Its innovative and visionary concepts are in the spirit of ADVENTURE.

MenuG is multidisciplinary (comprising biochemistry, molecular, structural and cell biology, medicine, biotechnology, nanotechnology); its truly ambitious goals can only be achieved at a European level by pooling expertise from academic and industrial units.

Call for proposal

FP6-2003-NEST-B-3
See other projects for this call

Funding Scheme

STREP - Specific Targeted Research Project

Coordinator

FOUNDATION FOR RESEARCH AND TECHNOLOGY - INSTITUTE OF MOLECULAR BIOLOGY AND BIOTECHNOLOGY
Address
Vassilika Vouton
Heraklion
Greece

Participants (5)

CELLECTIS S.A.
France
Address
102, Route De Noisy
Romainville
DIREVO BIOTECH AG
Germany
Address
Nattermannallee 1
Cologne (Köln)
INSTITUTE OF BIOTECHNOLOGY
Lithuania
Address
Graiciuno 8
Vilnius
JUSTUS-LIEBIG-UNIVERSITAT
Germany
Address
Ludwigstrasse 23
Giessen
UNIVERSITY MEDICAL CENRE GRONINGEN
Netherlands
Address
Hanzeplein 1
Groningen