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Model mice: Organism with neuro-degenerative pathology opens door to new therapeutics
May 2005
by Randall C. Willis  |  Email the author
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VERNON HILLS, Ill.—With an eye to developing therapeutics against neurodegenerative disease, Applied NeuroSolutions (ANS) recently joint-licensed a transgenic mouse line with the not-for-profit Research Foundation for Mental Hygiene at the Nathan S. Kline Research Institute that exhibits human disease pathology. According to ANS, the Htau mouse, developed by Dr. Karen Duff at the Nathan S. Kline Research Institute and Dr. Peter Davies of the Albert Einstein College of Medicine, is a step beyond existing model mice strains in better reproducing human Alzheimer's disease.
 
Under the terms of the agreement, ANS can use the Htau mouse for its own Alzheimer's drug development programs, and can sell sublicenses to other biotechnology and pharmaceutical firms in the market. In doing so, it would retain about half of the revenues generated by the secondary licenses.
This market could prove lucrative in the near future. A World Health Organization report suggests that by 2025, more than 34 million people will have Alzheimer's disease. Likewise, recent surveys suggest that the U.S. market for existing Alzheimer's medications may reach $2 billion in 2005.
 
A significant challenge that has made the development of effective drugs both difficult and expensive has been the lack of a suitable animal model for Alzheimer's disease.
 
"Looking at human post-mortem tissue is like looking at a car wreck after the accident and trying to work out if the cause of the accident was brake failure, or a steering strut broke," Duff says. She explains that the use of mouse models allows researchers to "order" and prioritize the events in the development of disease to target the earliest events better.
 
To create the Htau mouse, Davies and Duff inserted the human tau gene—a gene associated with the formation of neurofibrillary tangles in Alz-heimer's disease patients—into mice. This effort generated a transgenic mouse that closely mimics Alzheimer's disease pathology, both in the formation and location of neurofibrillary tangles, as well as in signs of neuronal degeneration and death.
 
The new model mouse also incorporates the regulatory machinery of the human tau gene, so the disease pathology manifests in the correct regions of the brain, a factor that will be critical to the development of drugs that target early stages of Alzheimer's progression.
 
"The mice start with normal brain pathology and the tangle pathology develops more slowly and with the correct distribution to model human Alzheimer's disease," Duff says. "Mutant models have abnormal brain pathology from birth and it progresses very fast, which might obscure subtle effects of therapeutics."
 
According to Duff, the creation of an accurate mouse model for Alzheimer's disease will have a significant impact in the development of treatments.
 
"By making different types of transgenic models, we have been able to demonstrate that phosphorylation of tau can trigger and exacerbate the disease process, thus making the development of therapeutics against phosphorylation (kinase inhibitors) more of a priority," she adds. "By creating mice with different parts of the pathology (plaques vs tangles), we can see that some drugs target both pathologies, making them potentially more useful that drugs that only target one pathology."
 
Code: E050514

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