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A Novel Anticonvulsant Drug |
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2DG (2–deoxy–D–glucose) is a chemical analogue of sugar which is
currently in preclinical development as a novel anticonvulsant and
antiepileptic compound for treatment of epilepsy. 2DG differs from
normal glucose only by removal of a single oxygen atom. As a close
chemical analogue of sugar, 2DG is taken up into cells by normal glucose
transport mechanisms, but unlike normal sugar cannot undergo metabolism
and acts as an inhibitor of glucose metabolism (glycolysis).
Studies at the University of Wisconsin have revealed that 2DG has novel acute and chronic anticonvulsant properties which are unlike any drugs currently available for treatment of epilepsy. 2DG acutely suppresses epileptic discharges in multiple experimental models of epilepsy, and has seizure–suppressing effects in a unique spectrum of animal models of epilepsy compared to currently marketed drugs. In addition to suppressing seizures, 2DG prevents the progression of the effects of seizures, which can include susceptibility to additional seizures, memory loss, and cognitive dysfunction. At the present time there are no anticonvulsant drugs on the market with disease–modifying properties which can favorably alter the consequences and prognosis for patients with epilepsy. Conventional anticonvulsant medications exert their therapeutic actions primarily by reducing the excitability of ion channels and synapses of neurons in the brain which can prevent or suppress seizures. In patients who fail to respond to conventional anticonvulsants, the ketogenic diet (replacement of carbohydrates with fats and proteins) sometimes produces improvement. The discovery of the therapeutic effects of 2DG was a result of efforts to investigate whether restriction of sugar and carbohydrate in this diet contributed to its actions. By blocking glycolytic metabolism of sugar, 2DG suppresses excitability in the brain leading to seizures, and also favorably modifies expression of neural genes in the brain contributing to the adverse consequences of seizures and long–term dysfunction associated with epilepsy. Because regions of the brain producing seizures have increased needs for energy and metabolic demand for sugar, 2DG preferentially accumulates in these regions during seizures. This unusual feature of loading into epileptic brain regions in response to metabolic demand offers an exceptional opportunity for novel methods of clinical delivery that could optimize its anticonvulsant action and minimize side effects. For example 2DG could be loaded into regions of the brain generating seizures when combined with therapeutic electrical stimulation through implanted brain electrodes which is currently in development and clinical trials. |
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The trapping of 2DG after uptake into cells has enabled its use as a
metabolic tracer for glucose utilization in human PET imaging and
scanning. Preliminary toxicity studies in animals also demonstrate that
2DG is well tolerated. With a record of safe use for decades in human
clinical imaging, favorable preliminary toxicity studies, and a unique
spectrum of protection in preclinical animal models of epilepsy, 2DG
appears to have potential as a therapy for epilepsy with novel
mechanisms of action compared to currently available anticonvulsants.
The Wisconsin Alumni Research Foundation (WARF), which holds the intellectual property rights for discoveries at the University or Wisconsin, has granted NeuroGenomex, Inc., an exclusive license for human therapeutic development of 2DG. This license includes not only epilepsy, but other disorders in which 2DG has demonstrated therapeutic potential including pain and cancer metastasis. As epilepsy affects about 1% of the population and these other potential therapeutic areas are significant, the market impact of successful development of 2DG could be considerable. |
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NeuroGenomex (NGX) is a pre–clinical drug development company engaged in
in–vivo validation of drugs to treat (CNS) central nervous system
disorders. NGX is currently advancing its lead drug candidate (2DG)
through independent pre–clinical trials in anticipation of filing an IND
application with the FDA leading to human trials.
In addition to providing a novel therapeutic approach for the treatment of epilepsy, continuing work at the University of Wisconsin, has shown promise for the application of 2DG to other disorders such as the prevention of cancer metastasis in which gene expression is regulated by glycolytic metabolism. The University of Wisconsin patents on all therapeutic applications of 2DG have been licensed exclusively to NGX, transferring more than 20 years of discovery and research knowledge in animal models of neural plasticity from the laboratory of NGX co–founder, Dr. Thomas P. Sutula. This proprietary technology has provided previously inaccessible in–vivo insights into molecular mechanisms of neural plasticity resulting in the identification of novel properties of 2DG. This includes a pattern of effectiveness that is quite distinct compared to currently FDA approved anticonvulsants. 2DG reduces the progression of seizures and this has a disease–modifying effect which not only suppresses seizures, but also modifies their potential to progress, thus reducing cumulative long–term, adverse consequences. No anticonvulsant drug currently on the market has disease–modifying effects which has been a long–sought goal of epilepsy therapeutics. In addition, none of the drugs currently serving the $12 billion epilepsy market are free of side effects, most of which are substantial and can be debilitating. |
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