From iPSC Disease Modeling to Epigenome Editing: Toward Therapeutic Reversal of Genomic Imprinting Disorders.

Abstract

Human induced pluripotent stem cells (iPSCs) and organoids are increasingly important components of new approach methodologies because they provide experimentally accessible human systems that preserve patient-specific genetic backgrounds and can be differentiated into disease-relevant cell types. Genomic imprinting disorders are particularly attractive targets for this approach because their pathogenesis depends not only on DNA sequence but also on parent-of-origin-specific epigenetic regulation. Prader-Willi syndrome (PWS) and Angelman syndrome (AS), which arise from distinct disruptions within the same imprinted domain on chromosome 15q11.2-q13, illustrate both the opportunities and the complexity of therapeutic epigenetic manipulation. Recent studies using PWS patient-derived iPSCs have shown that disease-associated imprinting states are largely retained after reprogramming and can be experimentally reversed by locus-specific epigenome editing. Targeted demethylation of the PWS imprinting control region restored multiple paternally expressed genes, and the corrected state persisted after differentiation into hypothalamic organoids, partially normalizing disease-associated transcriptomic and functional phenotypes. Here, we discuss how iPSC-based disease modeling is evolving from a platform for mechanism discovery toward a test bed for therapeutic epigenome engineering and outline the major challenges that must be addressed before epigenome editing can be translated to patients with imprinting disorders.