The essential strategy is that the use of gene transfer to bias the outcome of differential cDNA or proteomic screens in order to partially pre-validate targets as they are discovered. This is achieved by introducing an appropriate gene into the cells on one side of a comparison in order to bias the read-out towards genes that encode proteins that are active in the predefined disease process.
 

For example, consider a situation where a physiological stimulus, such as a cytokine, is central to a disease process and there is a desire to identify genes that are switched on by that stimulus as targets for product development. The "conventional" approach is to run a comparison of cells with and without the stimulus. The Smartomics approach is to transduce the cells that are going to receive the stimulus with a cassette that over-expresses the receptor for the cytokine. This would increase the signal to noise ratio of genes turned on by the cytokine/receptor pathway such that the read out would be biased heavily towards the desired genes. In addition the enhanced signal to noise ratio would increase the probability of finding small, but potentially important, differences that might be missed in the conventional approach. This general concept can be applied to many disease pathway scenarios that include the use of transcription factors, rate limiting steps in pathways and molecular ablation systems as well as receptor/ligand interactions. A key requirement of this approach is that the gene transfer technology that is used is phenotypically silent at the molecular level.
 

Pharmacom's gene discover program focuses on key disease related pathways in the fields of: oncology, inflammation, ischemic disease, and neurodegenrative disease.

Because of the insight inherent in our methodology the gene targets are to a degree pre-validated and thus have a higher probability of being mechanistically linked to the pathological processes in the diseases under study. Further validation is conducted using in vitro and in vivo assays and LentiVector, or other in-house gene transfer technology, to transfer the candidate genes or anti-sense into appropriate cellular environments, notably non-dividing primary cells, including, eg, macrophages, cardiomyocytes and many types of neuronal tissue. Pharmacom has expertise with a wide range of cellular assays for inflammation, tumour development, Stroke, apoptosis and atherosclerosis. In addition we have developed a gene transfer system for neuronal tissue in vivo where reliable, safe long-term expression is desirable. For Stroke target validation, Pharmacom has developed model systems and appropriate ischaemic-neuronal cell assays. Transduction efficiency and a lack of cellular toxicity are hallmarks of the current gene transfer system -particularly important in sensitive cells such as neurons and where it is critical that there is no interference of cellular activity due to virally expressed genes.