Aging Ku80 Knock-Out Mice Linked to p53

<%=company1%> (The Woodlands, TX) has found that a gene that controls how quickly mice age functions as part of the p53 pathway, one of the more commonly mutated genes in human cancers. Using proprietary technology, Lexicon scientists knocked out the Ku80 gene in mice, which resulted in mice that aged more than twice as fast as normal mice. The knockout mice had an average life span of only nine months, compared to about two years for normal mice. The Ku80 gene was found to be in a cellular senescence pathway controlled by the p53 tumor suppressor gene. The work was published in the latest issue of the journal Molecular and Cellular Biology.

"These knockout mice give us a unique window on the pathways controlling aging and cancer for the development of new therapeutics against aging and cancer. This remarkable early-aging phenotype, caused by the loss of a single gene, demonstrates the power of our knockout technology to discover medically important functions of genes," said Arthur T. Sands, president and CEO of Lexicon and co-author on the publication.

The company was issued a broad U.S. Patent covering Ku80 knockout mice in September 1999, based on research with Ku80 knockout animals which was published in Proceedings of the National Academy of Sciences, also in September 1999. The latest studies demonstrate the Ku80 gene not only controls the rate at which whole animals age, but also functions in a pathway with the p53 tumor suppressor gene.

Ku80 Knockout Phenotype
By six months of age, the Ku80 knockout mice appear old and display many characteristics of normal mice of more than twice their chronological age, including bone weakness, thinning of the skin, hair loss, and susceptibility to infection. Consequently, the life expectancy of Ku80 knockout mice is dramatically shortened due to a spectrum of age-related problems that are triggered by loss of the gene's normal function. In addition, Lexicon scientists crossed mice lacking the Ku80 gene with mice lacking the p53 tumor suppressor gene and discovered that cells from these double knockout mice did not age prematurely, but the animals still developed cancer.

The normal mouse (left) is chronologically older than the knockout mouse (right) lacking the Ku80 gene; however the knockout mouse has biologically aged at more than twice the normal rate. (PRNewsFoto)

Mouse and human Ku80 are 85% identical and have the same biochemical function (human Ku80 can substitute for mouse Ku80 in mouse cells deficient for Ku80). Ku80 functions in DNA repair, and defects in this pathway have been associated with diseases, specifically with severe immunodeficiency syndromes. The company also recently was issued a U.S. Patent covering the use of another DNA repair protein, known as Rad51, a potential target of cancer therapeutics implicated in breast and ovarian cancer.

Lexicon's Knockout Technology
Lexicon uses proprietary gene targeting and gene trapping technologies to rapidly create knockout mice for use in drug discovery. Using its proprietary gene targeting technology, Lexicon has created more than 70,000 knockout mouse clones. Lexicon has invented high-throughput gene trapping technology to discover thousands of genes and expand its OmniBank library of tens of thousands of knockout mouse clones. The company uses an integrated platform of functional genomic technologies to accelerate large-scale analysis of mammalian gene function for drug discovery. Through Lexicon's Internet exchange, Lexgen.com, researchers can access the OmniBank library and form collaborations with Lexicon to discover pharmaceutical products based on genes and knowledge of their functions.

Lexicon has established functional genomics and OmniBank alliances with many pharmaceutical and biotechnology companies including American Home Products, The R.W. Johnson Pharmaceutical Research Institute, G.D. Searle & Co., Boehringer Ingelheim Pharmaceuticals, N.V. Organon, ZymoGenetics/ Novo Nordisk, DuPont Pharmaceuticals, and Millennium Pharmaceuticals.

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

Edited by Laura DeFrancesco