Prader-Willi Syndrome (PWS) and Schaaf-Yang Syndrome (SYS) are neurodevelopmental disorders caused by absence of expression of paternally inherited gene(s) at the imprinted PWS cluster on chromosome 15. All individuals living with these disorders possess a normal but epigenetically repressed maternal copy of affected genes, which offers an opportunity for therapeutic intervention. SMCHD1 is an epigenetic repressor, targetable by small molecules and known to play a role in silencing the PWS cluster. We are working on proof-of-concept data for gene activation using SMCHD1 as a target for potential therapy. Removal of Smchd1 in vitro has been shown to result in activation of the silent maternally inherited copy of PWS genes. Using both allele-specific RNA sequencing and a reporter mouse model for Magel2 expression we have shown that, in line with previous data, deletion of Smchd1 can result in activation of maternally inherited PWS genes in vivo in the brain. To determine whether the level of activation we observe is sufficient to rescue disease phenotypes in the Magel2 paternal-null mouse model of PWS and SYS we have have begun behavioural and motor testing using mice that have had Smchd1 deleted in the brain. Looking at features of PWS within the pilot cohort we have observed some phenotypic rescue in the Smchd1 deleted PWS mice compared with their disease and control littermates and are planning future cohorts to further measure these effects. From this we aim to increase understanding of the molecular mechanisms at work within the PWS cluster and to confirm viability of SMCHD1 as a target for epigenetic therapy of PWS.