The development of targeted epigenetic approaches targeting human PRNP, as well as validation of the long-term durability of CHARM-mediated epigenetic silencing in vivo, understanding the extent and consequences of off-target methylation and silencing, and characterizing efficacy against prion disease progression, would further advance the therapeutic relevance of epigenetic approaches, which offer strengths that complement those of gene-editing approaches. The gene discussed is PRNP; the disease is prion disease.