GENESIS is a virally-mediated homologous recombination technology that is orders of magnitude more efficient in performing gene-targeting in somatic human cell-types over previous plasmid-based technologies.

Targeting Vectors 1995 - 2005

Plasmid-based homologous recombination techniques have been used primarily to create transgenic mice from embryonic stems cells (an approach that received the Nobel Prize in 2007 for Mario R. Capecchi, Sir Martin J. Evans and Oliver Smithies). However, in these cell-types, recombination frequencies are naturally very high to support DNA repair during cell-division; whereas in non-dividing or differentiated somatic cell types, this process is essentially shut off.

This has been a serious restriction in creating genetically defined human disease models; where one cannot utilise the natural process of homologous recombination to precisely and permanently alter any target endogenous gene in the human genome, without eliciting unwanted off-target genetic changes or integration-site errors.

Older DNA plasmid-based vectors are too bespoke, inefficient and variable in their success rates to attempt gene-targeting on a commercial scale. Nevertheless, over a period of 15 years, a significant bank of genetically-defined mutant versus normal human cell-lines has been assembled by various research groups and these have now been exclusively in-licensed by Horizon and are being marketed under its X-MAN™ brand.

Targeting Vectors 2005 Onwards

In order to create a more robust future source of genetically-defined human cell-lines, a revolutionary technology advance was needed; ideally one that achieves the high levels of homologous recombination readily seen in murine stem cells. To realize this aim, Horizon has applied a seminal discovery by Professor David Russell that suggested that certain Adeno-Associated Virus (AAV) homologous recombination vectors comprising single-stranded homologous DNA were far more efficient at gene-targeting in human somatic cell-types over older DNA plasmid-based vectors containing double-stranded homologous DNA (even when promoted by zinc finger or meganuclease delivery).

The use of AAV vectors in gene-targeting was subsequently reduced-to-practice by Horizon’s collaborators and co-founders; and the world-wide patent estate underpinning its use in all in-vitro applications was exclusively in-licensed from the University of Washington for marketing under the GENESIS brand.

Horizon are now using this ‘gold standard’ gene-engineering platform to routinely, stably and precisely engineer a wide-panel of cellular models of genetically-defined human disease states, as well as provide their perfectly matched normal genetic backgrounds as a reference.

GENESIS has received international acclaim and has been honoured at the 2008 Medical Futures Innovation awards; the 2009 iawards and 2010 East of England Business Awards as a truly innovative and disruptive technology.

References

• Featured publications
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Downloads

• Horizon Technology Presentation
• X-MAN and GENSIS FAQs