Project: Interrogation of Somatic and Inherited Gene-variations for Human Therapy

Genetic variations, whether they are inherited or acquired as we age, play a significant part in the incidence and severity of almost every human disease._x000D__x000D_Recent advances in high-throughput DNA-sequencing now afford a detailed view of human genetic variation, plus the ability to quickly assess an individual's own ‘SNP’ profile; however, much work is still needed to link specific genetic markers with disease risks, or in directing therapy._x000D__x000D_Predictive and genetically-defined in vitro human disease models are a key missing link in achieving these goals; and such models ideally need to be generated prior to an individual’s disease or therapy onset. However, until recently, the methods available to ‘pre-engineer’ genetically-defined human disease models in vitro, have not been robust or reliable in their performance. _x000D__x000D_Horizon Discovery and Professor Tobias Sjöblom are experts in using a novel and proprietary AAV-virus mediated method of in vitro gene-engineering, which for the first time allows the efficient, precise and stable alteration of any endogenous gene in a normal human cell-line. _x000D__x000D_Using this technology, a large panel of normal vs cancer disease models have been created, which are rapidly being adopted by academic and industrial researchers as gold standard tools to study cell function and develop novel ‘personalised’ therapies. _x000D__x000D_The aim of the ‘INSIGHT’ project is to develop new ‘product-lines’, based on a recent and seminal discovery that "non-protein coding"; somatically acquired (i.e., non-inherited), genetic variations may cause cancer. This novel finding that acquired DNA-variations occurring in potential gene regulatory regions (e.g.,promoters, splicing sites and chromatin remodelling sites) may represent key cancer drivers, is one that demands further study and if validated will become a major focus for future therapeutic targeting. _x000D__x000D_With special importance to this project and our expertise, such novel non-coding gene-variations must be introduced and studied in the endogenous genomic context (wherein all the proximal and distal regulatory mechanisms reside) and this can only be routinely and rapidly achieved using our proprietary technology. _x000D__x000D_The ‘INSIGHT’ project will be composed of three highly focussed activities that build on established expertise and technologies:_x000D__x000D_1) The generation of novel inherited and somatic non-coding mutation disease models for commercialisation by Horizon Discovery. _x000D__x000D_2) The screening of non-coding somatic mutations in a wider range of cancers; building our profile, public information and future IP in a major new R&D field._x000D__x000D_3) The profiling of all known cancer drugs for their activity on cells carrying these novel cancer mutations, to discover potential new therapeutic options for patients that can be studied in clinical trials. _x000D__x000D_Horizon Discovery are well-versed in performing in vitro gene engineering and drug screening, whose genetically defined disease models are leading to changes in drug development and prescription, such as Erbitux in colon cancer (deRook, W. JAMA. 2010 Oct 27;304(16):1812-20); and Tobias Sjöblom is a leader in the field of cancer genetics.

Acronym	INSIGHT (Reference Number: 6548)
Duration	01/07/2011 - 30/06/2014
Project Topic	Using established expertise in cancer genetics and a proprietary technology to perform in vitro gene-engineering, we will create a new range of predictive human disease models carrying novel genetic variations, to support research into disease causation and the discovery novel targeted therapies.
Project Results (after finalisation)	Genotyping of polymorphisms as stated in the application. Generation of genetic models of genes (DIP2C, ZBED6, PRDM2) as stated in the application and co-funding agreements between us and Horizon Discovery Ltd. Algorithms for large scale design of AAV KI/KO constructs (included in co-funding agreements, not complete)
Network	Eurostars
Call	Eurostars Cut-Off 6

Project partner

Number	Name	Role	Country
2	Horizon Discovery Ltd	Coordinator	United Kingdom
2	Uppsala university	Partner	Sweden