About Knockout Mice
We use knockout mice whose DNA has been modified to disrupt, or "knock out," the function of the altered gene.  Using our patented gene trapping and gene targeting technologies, we generate and study knockout mice to discover the physiological and behavioral effects that result from the disruption of a single gene.  Because there is a close similarity in gene function and physiology between mice and humans, with a large majority of human genes having a counterpart in the mouse genome, knockout mouse technology has become a powerful tool in the discovery of new medicines.

Proven Technology
The value of our technology in drug discovery has been described in a large body of scientific literature which was reviewed in a retrospective analysis we performed on the 100 best selling drugs of 2001 and their targets, as modeled by the physiological characteristics of knockout mice.  This analysis was published in the January 2003 issue of Nature Reviews Drug Discovery, a peer-reviewed scientific journal.  In this analysis, we concluded that in most cases there was a direct correlation between the physiological characteristics, or phenotypes, of knockout mice and the therapeutic effect of the 100 best-selling drugs of 2001.  The tremendous utility of knockout mouse technology was recognized in 2007 with the Nobel Prize in Physiology or Medicine to Drs. Mario Capecchi, Martin Evans, and Oliver Smithies.  In awarding this prize, the Nobel committee stated that, “Almost every aspect of mammalian physiology can be studied by gene targeting” and that, “[This] immensely powerful technology… [is] now being applied to virtually all areas of biomedicine – from basic research to the development of new therapies.”

Identifying the Best Drug Targets
We employ an integrated platform of physiological analysis technologies to systematically discover, within a living organism, the physiological and behavioral consequences that result from the loss or inactivation of a specific gene, and to assess whether or not the potential drug targets—the proteins encoded by the human version of the genes—will have pharmaceutical utility.  Since most drugs act as antagonists or blockers of their targets, we interpret mouse knockout phenotypes as living models of future drug action in an idealized state of complete inhibition of target function. In other words, it is as if the knockout mouse is on a drug that is 100% potent and 100% specific.  This allows our scientists to make predictions about what an actual drug would do, before we invent it.  If the results indicate it would be desirable to augment rather than inhibit the target of interest, we then consider designing agonists or activators of the target, or if feasible, supply the protein itself as a replacement therapy.

The power of this approach is amplified as we have applied it on a genomic scale. Since the druggable genes encode all potential human target proteins and the vast majority are of unknown function, knocking them all out one by one enables us to model what any drug would do before we invent it.  In this manner, Lexicon has gained tremendous insight into the genome and our scientists are able to select the most desirable targets for the creation of future breakthrough drugs.

We believe that our technology platform and medical approach to target validation provides us with substantial advantages over other approaches to discover gene function and identify novel drug targets.  In particular, we believe that the comprehensive nature of our approach allows us to uncover functions within the context of mammalian physiology that might be missed by more narrowly focused efforts.  We also believe our approach is more likely to reveal those side effects that may be a direct result of inhibiting or otherwise modulating the drug target.  Such target-related side effects might limit the utility of potential therapeutics directed at the drug target or prove to be unacceptable in light of the potential therapeutic benefit. We believe these advantages will contribute to better target selection and, ultimately more successful drug discovery and development.