AN HDAC APPROACH TO RETT SYNDROME

Disease modifying therapies are needed for the treatment of Rett syndrome RTT as there are no current medications that get to the core of disease pathology Our ongoing work on the design of selective HDAC inhibitors HDAC i offers a truly innovative approach to the possible treatment of RTT as it begins to tackle cellular deficits we have identified that arise due to improper MeCP function The preliminary data we have generated demonstrating the ability of an HDAC i to reduce seizures in Mecp mutant mice and improve their rotarod behavioral performance provide a strong foundation for pursuing an HDAC i based approach for treating RTT individuals The innovative aspects of the present undertaking encompass both the chemistry and the biology Our research program will allow us to refine lead HDAC i candidates using in vivo and in vitro assays in Mecp deficient mice and neuronal cultures and to obtain valuable ADMET data to aid the translation of this class of molecules to the clinic Accordingly our working hypotheses are that upregulated HDAC activity contributes to RTT symptomatology and that pharmacological inhibition of HDAC will prevent the development and or reverse the RTT like phenotypes in Mecp deficient mice Thus in our quest for effective RTT therapeutics we propose a plan of research that encompasses the following aims Specific Aim Scale up highly selective Tetrahydroquinoline based HDAC i to allow for testing in MeCP deficient cells We have designed and synthesized certain tetrahydroquinoline THQ containing HDAC is like SW that possess low nM inhibitory activities and in most cases possessing high selectivity andgt fold against HDAC SW is negative in the Ames test although improvements in its metabolic half life should be sought As SW is readily able to penetrate the BBB and has shown efficacy in Fragile X animals we believe it is a good candidate for further optimization and study in the Rett animals Based on in silico ADMET calculations we have generated new analogs that possess comparable or improved HDAC i potency The analogs will be scaled up and screened further for their ability to enhance acetyl tubulin levels and to improve mitochondrial trafficking in cultured neurons from Mecp KO mice The top compounds showing the best cellular activity will then be submitted for ADMET testing in order to ensure acceptable brain PK lack of Ames and hERG activity low inhibition of the CYP enzymes etc See Table X for desired ADMET parameters Specific Aim Next after completion of the ADMET tests the two best compounds from Aim will be studied for their ability to correct the hypo acetylated tubulin phenotype present in the brains of symptomatic male Mecp KO and female Mecp heterozygous Het mice and reduce the incidence rates of their andquot Rett likeandquot epileptiform discharge activity Any signs of adverse events associated would compound toxicity would be noted although to date the compounds in this class have not raised safety concerns Rett syndrome RTT is a devastating genetic condition that affects mostly girls at a young age it is one of the worst types of neurodevelopmental disorders and at present there are no effective treatments or cures To facilitate developing treatments MeCP based mouse models of RTT syndrome have been developed and we have been using these models to identify functional deficits that we hypothesize are responsible for causing the behavioral and physiological impairments seen in RTT individuals Our work has identified a novel molecular system as a strong candidate for therapeutic intervention histone deacetylase type HDAC is over represented in RTT mouse brains and as such its activity is also above normal levels Our goal is thus to identify brain penetrable HDAC inhibitors that can be used to prevent and or revert RTT like deficits in Mecp deficient mice