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SNIPER — Result In Brief

Project ID: 5204
Country: Norway

Highly specific gene transfer

A new method for in vivo genetic engineering has come to revolutionise gene targeting and shows great potential for somatic gene therapy.
Highly specific gene transfer
Direct modification of a target gene at its genomic location, without the introduction of additional redundant sequences, offers an appealing strategy for gene therapy. Gene targeting has been made possible with sequence-specific DNA-binding ligands such as single-stranded oligonucleotides (ssODNs), triple-helix–forming oligonucleotides (TFOs) and peptide nucleic acids (PNAs).

Partners had previously developed a gene-targeting method of using oligomers (ROs) composed of two functional domains. The targeting domain provides high sequence affinity to a desired location in the genome, and the template domain activates the cellular repair machinery to induce small sequence changes without leaving foreign sequences.

The goal of the EU-funded ‘Sequence specific oligomers for in vivo DNA repair’ (Sniper) project was to further improve the design of this oligomer platform technology so as to induce precise single-base changes in a cell culture readout at improved rates.

For this purpose, project partners studied the biological parameters involved during the genomic changes induced by ssODNs. They also modified the bases in the TFOs to increase triplex stability and binding kinetics.

Additional molecules explored by the consortium for recognising DNA and inducing recombination included PNAs and zinc finger nucleases (ZFNs). ZFNs constitute artificial restriction enzymes generated by fusing a zinc finger DNA-binding domain to a DNA-cleavage domain engineered to target desired DNA sequences.

Collectively, all the DNA-binding ligands tested during the Sniper project exhibited the potential of site-targeted DNA sequence alterations and hence gene repair. The applications of these oligomers are quite broad and except for research purposes, it is envisaged that they can be used as alternative means of gene transfer.

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