COPDETOX

Metal overload plays an important role in several diseases such as Wilson’s disease, a major genetic disorder of copper metabolism in humans. The Wilson’s disease is a rare disease (~ 1000 cases in France, 10000 in the EU and 10000 in the USA) due to the lack of a protein responsible for the excretion of excess copper from the body. It results in an hepatic copper overload that is lethal if not diagnosed. The current treatments are poorly selective for copper and induce major side effects. It is therefore a societal issue to design innovative chelators that are (i) highly selective for copper to avoid disturbance of other essential metals like zinc and (ii) targeted at the liver, where copper is accumulated, to avoid copper chelation at other places in the body. In our laboratory, we are developing efficient copper chelators, some of them coupled to liver-targeting units. Some of them were shown to enter hepatocytes and to lower the intracellular copper concentration; they are thus good candidates to eliminate copper from the liver. This proposal aims at optimizing in vitro and validating in vivo such efficient copper chelators as potential and innovative drugs to treat people suffering from copper overload such as Wilson’s disease patients. Two patents are already held for the chelating and therapeutic activities of the molecules from two families and we are now willing to get the proof of concept done on animal models. A first compound will be tested soon in vivo after we get financial support from GRAVIT (http://www.gravit-innovation.org/) in April 2011. Another compound of even higher affinity for copper, will be evaluated in the present COPDETOX project. It will be given to healthy rodents to check their tolerance to the molecule and to Wilson’s disease model rodents to test its efficiency by comparison with the chelator currently prescribed. Another important step will be to optimize the chelator chemical structure and the targeting unit to get even more efficient molecules. The best candidates selected in vitro will be tested using cell culture and when appropriate in vivo, using animal models such as LEC rats or atp7b-/- mice. Toxicity studies will then be envisaged. The outcome expected from this project is the proof that liver-targeted copper chelators are able to promote copper excretion in Wilson’s disease animal models with minimal side effects and toxicity. We should have enough data to interest some drug companies involved in the rare disease field.