Nonsense Suppressing Drugs for Rett Syndrome

Nonsense Suppressing Drugs for Rett Syndrome Rett syndromeRTTis a devastating genetic condition that affects mostly femalesIt is one of the worst types of neurodevelopmental disordersthe affected girls are born without any obvious problemsdevelop in a seemingly typical manner for the first year of lifebut then abruptly and without warning lose most of their acquired abilitiesRTT girls then typically develop irregular breathing patternsfail to develop speechlose purposeful hand movementsbegin showing autism like behaviorsfrequently develop epilepsyand often have difficulty eating and digesting foodRTT individuals exhibit a highly variable lifespanand are at risk for sudden an unexpected deathAt present there are no effective treatments or curesdespite the prevalence of RTT being more common than the rate of paralytic spinal cord injury in the general populationworld wideThe majority of Rett syndrome cases are caused by mutations of the X linked gene encoding methyl CPG binding proteinMECPProper function of MeCPis essential for normal nerve functionand is required for CNS maturationImportantlythe condition is not irremediablerestoring MeCPfunction in already symptomatic MeCPdeficient mice rescues their RTT like conditionThis observation highlights the need to develop treatment strategies that can restore MeCPfunction in affected individualsDrugs that facilitateread throughof nonsense mutations of MECPrepresent an attractive possible treatment strategy and based on our preliminary data we are convinced that effective nonsense suppressing drugs can be developed to allow successful treatment of approximately one third of all RTT casesThe goals of this project are to develop newread throughdrugs with better efficacy and lower toxicityTo accomplish these goals we will carry out the following aimsIdentify and or generate newread throughdrugs with improved properties for CNS applications by using rational drug design methods starting from selected RT ligands that we have shown to be capable of inducing expression of the MeCPproteinDetermineread throughefficacies and assess the functionality of the restored MeCPproteinThe novel drugs from Aimwill be tested forread throughactivity against the six most common MECPnonsense mutations seen clinically using in vitro transfection assays in HEKcellsDetermine ADME properties of analogs including brain PKCacopermeabilityCyp inhibitionmicrosomal stabilityAmes and hERG activityDetermine in vivoread throughactivity of analogs in brainThe topread throughanalogs displaying the best in vitro efficacy from Aimand brain penetrance values from Aimwill be tested for brain activity in vivo using a custom nonsense mutation mouse model Rett syndromeRTTis a devastating genetic condition that affects mostly femalesIt is one of the worst types of neurodevelopmental disordersthe affected girls are born without any obvious problemsdevelop in a seemingly typical manner for the first year of lifebut then abruptly and without warning lose most of their acquired abilitiesWe believe that nonsense suppressing drugs can be developed to allow successful treatment of approximately one third of all Rett syndrome cases that are due to the presence of premature stop codons in the MecPgeneThese efforts will focus on the design of new read through drugstheir testing in cellular systemswith the final goal of testing the most favorable candidates in animal models of Rett syndrome