[ANR] Patrick Vourc'h - WALKIn - Development of a new treatment for ALS through LIMK Inhibition, key regulators of actin dynamics

WALKIn - Development of a new treatment for ALS through LIMK Inhibition, key regulators of actin dynamics

The dynamics of the actin cytoskeleton is of growing interest in the study and treatment of neurodegenerative diseases, in particular amyotrophic lateral sclerosis (ALS, Charcot's disease), where it is altered. ALS is a characterized by the death of upper and lower motor neurons which has no cure. A very recent clinical trial testing an inhibitor of the ROCK protein, which blocks the RhoA/ROCK signaling pathway and activates actin depolymerization, has shown promising results in ALS patients. However, the ROCK protein is located upstream of many cell signaling pathways, which may explain why and ROCK inhibitors have side effects. The aim of our project WALKin is to develop specific and selective inhibitors of LIM kinases 1 and 2 (LIMKs), key regulators of actin dynamics. These LIMKs are particularly appropriate targets in ALS, as they are downstream of the RhoA/ROCK signaling pathway, but also of other Rho-GTPase pathways such as Rac1 and Cdc42, which are also altered in ALS. Our project is therefore motivated by the fact that treating ALS or preventing it in presymptomatic individuals by targeting altered actin dynamics, will certainly require acting simultaneously on several pathways, not just RhoA/ROCK. The preliminary results we have obtained on a new LIMK inhibitor we have patented fully support this idea. By choosing to target LIMKs, we therefore hope to amplify the encouraging results on neuronal preservation and survival recently obtained with a ROCK inhibitor administered to ALS patients. The new inhibitors of LIMKs could also be useful for other neurodegenerative diseases with abnormal actin dynamics.

PI - VOURC'H Patrick, UMR iBraiN, Université de Tours, Inserm

Partenaires - ROUTIER Sylvain, UMR ICOA, CNRS/Université d'Orléans & VALLEE Béatrice, UPR CBM, CNRS, Orléans