Abstract
Genomic imprinting disorders (IDs) arise from the disruption of parent-of-origin-specific gene expression, a process governed by heritable epigenetic marks. Conventional therapies are largely symptomatic and fail to correct the underlying defect in dynamic gene regulation. Epigenome editing, using programmable DNA-targeting tools to rewrite epigenetic information, has emerged as a powerful therapeutic strategy that directly addresses this molecular pathology. This review synthesizes the transformative progress of the past decade, arguing that epigenome editing is poised to revolutionize the treatment of these conditions. We detail key breakthroughs in both editor design and in vivo delivery. These include the development of next-generation editors, such as compact "hit-and-run" systems that establish durable epigenetic memory after only transient expression-a critical feature for clinical safety. We then examine parallel advances in delivery platforms, including engineered adeno-associated virus (AAV) vectors with enhanced central nervous system (CNS) tropism and programmable lipid nanoparticles (LNPs) for precise extra-hepatic targeting. The therapeutic potential of combining these technologies is underscored by convincing preclinical data in models of Angelman (AS) and Prader-Willi syndromes (PWS), where the targeted rewriting of epigenetic marks has successfully reactivated silenced alleles and rescued disease-relevant phenotypes. Finally, we discuss the remaining challenges-including long-term durability and off-target safety-that must be overcome to translate this scientific potential into transformative medicines.