Lexicon Genetics Introduces Rapid Method for Accelerating Drug Discovery

Lexicon Genetics Inc. (The Woodlands, TX) has introduced a new approach to understanding the function of human genes and in validating potential drug targets using Lambda KOS, the company's proprietary gene targeting and gene replacement system. Lambda KOS, a component of Lexicon's genetic engineering technology portfolio, streamlines and accelerates drug discovery by identifying gene function and determining the roles genes play in various human diseases. Lambda KOS incorporates a yeast shuttle vector system used to rapidly create several manipulations of the mouse genome including point mutations, conditional knockouts, null alleles, and humanized alleles. The technology is described in the June, 1999 issue of Biotechniques [26(6):1150-1160].

"Identifying valid drug targets is one of the critical issues in developing new therapeutics," said Arthur Sands, president and CEO of Lexicon Genetics. "The Lambda KOS system provides the flexibility to rapidly alter virtually any gene in any way to accelerate the drug discovery process, providing an important advantage in the race to understand the human genome."

Lexicon's Lambda KOS system has already been used to mutate gene targets and expedite drug discovery through creation of knockout mice, as exemplified by agreements with Merck & Co. Inc., ZymoGenetics Inc., Genetics Institute, Cephalon, H. Lundbeck A/S, The Rockefeller University, Tufts University, University of Rochester, and many others.

Lambda KOS was developed by Michael Nehls and Sigrid Wattler, two scientists at Lexicon. The method incorporates a proprietary, arrayed genomic library that facilitates gene cloning in less than a week, with near simultaneous transfer to plasmid vectors. Lambda KOS thereby eliminates tedious conventional molecular cloning techniques: The plasmid vector undergoes homologous recombination in yeast host cells to generate a complete gene targeting or gene replacement vector that is ready for immediate use in mouse embryonic stem cells. Click here to see a diagram of the Lambda KOS system.)

Traditional methodology takes several months to screen genomic libraries before construction of knockout vectors. With Lambda KOS, Lexicon can complete a gene-targeting vector in less than three weeks, thus providing a rapid route to drug discovery. Lexicon can leverage Lambda KOS to generate a wide variety of vectors for introducing such gene modifications as point mutations, humanized alleles. With the Cre/loxP recombinase system licensed from DuPont, Lambda KOS can also handle conditional mutations.

Lambda KOS incorporates the advantages of several modern technologies such as PCR-based screening of arrayed genomic libraries, CRE/lox-mediated plasmid conversion, and restriction-independent target vector construction by yeast-mediated homologous recombination, as well as positive/negative selection in embryonic stem cells. Said Nehls, "Lambda KOS enables Lexicon to generate mice with predefined mutations at an unprecedented speed. In effect, we can go from library screen to ES cell electroporation in three to four weeks, at whatever level of mutation specification is desired."

About Lexicon
Lexicon is a privately held company based in The Research Forest biotechnology community of The Woodlands, TX. Lexicon currently has 100 employees and occupies over 65,000 square feet of state-of-the-art genomic research laboratories. Included in that space is a 30,000 square foot vivarium that can house up to 70,000 genetically engineered mice with facilities to conduct rapid in-vivo biologic target validation using phenotypic screens.

Lexicon's discovery programs include:

E-N-Compass. E-N-Compass provides discovery opportunities through Lexicon's proprietary OmniBank and the Human Gene Trap databases. This program provides Lexicon's partners access to its STV Program for high throughput in vivo biological validation for numerous drug targets of interest to our partners, and rapid production of custom knockout mice.

OmniBank Subscriptions. These subscriptions provide Internet access to OmniBank using Lexicon's web-based bioinformatics software. Subscribers can select from over 40,000 genetically modified mouse clones using DNA homology comparisons or key word searches.

STV (Seek Target Validation). STV provides high-throughput target functional analysis through a focused set of phenotypic screens designed to rapidly assay the major physiologic systems of genetically altered mice. Biological and pre-assay development reports are provided to Lexicon's partners for each drug target analyzed.

RepairDNA. RepairDNA is a multi-faceted, functional genomics research program to discover biologically validated targets for cancer therapy. Using the STV Program rationale, Lexicon has already developed one validated DNA repair target and potential cancer therapeutic, which is a current product partnership opportunity.

ResKU. ResKU is a functional genomics research program to discover targets on the aging pathway using one of Lexicon's proprietary knockout mice that exhibits a greatly accelerated senescence phenotype. This knockout-based senescence research program will be available for partnering for the first time in 1999.

Homologous Recombination. Homologous Recombination is used for rapidly producing custom knockout mice, conditional gene knockouts (using recombinase technologies), and point mutations for specific drug targets. Lexicon is fully licensed for the use of Cre/loxP recombinase technology for creating conditional mouse knockouts.

For more information: Lori Pinkerton, Lexicon Genetics Inc. 4000 Research Forest Dr., The Woodlands, TX 77381-4287. Tel: 281-364-0100. Fax: 281-364-0155.