Reference:
ANRn.a.8-BIOTn.a.020
Abstract:
Rett syndrome (RS) is a severe neurological disorder caused by a mutation in the MECP2 gene transcriptional repressor. SR girls develop normally until 6-18 months later, they suffer neurological symptoms and severe respiratory ?irregularities. So far no treatment is available. Previously, using a mouse model of SR, we have shown that disruption of the respiratory control come from ?a gradual deficit contained in noradrenaline (NA). By treating mutant mice with a specific inhibitor of the reuptake of NA, desipramine, we could reduce respiratory and we could extend their lifespan. Then we conducted a clinical trial with SR girls who just started. The objective of the current consortium is to develop a new treatment in the SR. To achieve this goal we associate Targeon skills, which will be responsible for ?identification and synthesis of selected candidate molecules and the team of Dr. Laurent Villard, who is responsible for them and in vivo evaluation cell. The purpose of this project is to obtain a candidate molecule ?giving full satisfaction on preclinical models. If this is the case, ?objective of the consortium will be the establishment of a clinical trial ?Phase IIa proof-of-concept. Partner 2 has already proved that ?a novel approach in the SR could provide essential pathophysiological information. Using a mouse model SR team was the first to characterize the development of respiratory problems and their probable origin knowing that respiratory irregularities are responsible for 25% of sudden deaths in the SR. The partner.2 also identified the first cellular deficiency in a population of catecholaminergic neurons in the brainstem and has developed an effective treatment, using desipramine, significantly increasing the survival of mutant mice. A patent on the use of desipramine to treat self-disorders in the SR was filed by INSERM ?(WO2007019880). These results led to Partner 2, and the team Pr Josette Mancini ?s AP-HM obtain funds to start a Phase IIa clinical trial in SR with desipramine (National PHRC n ﾰ 24n.a.3 ). Similarly, if desipramine, our candidate ??first generation molecule represents a potential treatment of disorders of autonomic function in the SR, new molecules having a different mode ?action, greater efficiency or a better efficacy / safety ratio must be developed. This project will be carried out between the following partners: Partner 1: Targeon is a biotechnology company specializing in the development of new therapies for orphan diseases. Its founder, Dr. Hugues Bienaym�, worked for 17 years in the discovery of new molecules. He has held various positions in Aventis, Pierre Fabre and Urogene companies. partner 2: Team Laurent Villard has already identified the first cellular deficiency in the mouse model of RS. It also proposed the first effective treatment in these mice SR to prolong their life. Finally, the team is involved in the establishment of the first clinical trial double-blind girls SR. Our project consists of three major parts, or work packages: WP1) We will choose and synthesize 5-7 drugs or drug candidates in sufficient quantities to undertake in vivo and cellular evaluations. ‘s drug candidates will be selected for their action on the bioamines metabolism. In particular, we focus on the following therapeutic classes: bioamines precursors, inhibitors of degradation bioamines, Inhibits the
PROJECT DETAILS
beginning: 2008.
end: 2011.
Country of research: France
Counry of funding source: France
Funding organization: The French National Research Agency
Financing: NATIONAL FUNDINGS – 439 643 €