Prader-Willi syndrome (PWS) is a neurodevelopmental disorder arising from lack of gene expression at the imprinted PWS cluster. Patients with this disorder all retain a normal yet epigenetically silenced copy of PWS genes. We are investigating SMCHD1, a known epigenetic repressor with a role in silencing at the PWS locus, as a potential target for gene activation therapy in PWS patients. Using mouse models we have been able to confirm activation of PWS genes in relevant brain regions upon Smchd1 deletion in vivo. Preliminary data from functional studies suggests the PWS gene activation we can achieve leads to functional improvement in phenotypes in a mouse model of PWS. We also observe gene activation upon SMCHD1 depletion in human patient-derived cells, which taken together lends support to the viability of SMCHD1 as a target for epigenetic therapy of PWS.