Targeted Epigenetic Reactivation strategies as new treatments for Prader-Willi Syndrome: Achievements and Challenges.

Abstract

Prader-Willi Syndrome (PWS) is a genetic neurodevelopmental disorder caused by the loss of expression of paternal genes in the 15q11-q13 locus. The same genes on the maternal allele are present but are epigenetically silenced. This genetic alteration causes a spectrum of symptoms associated with hypothalamic dysfunction. Research is increasingly focused on setting strategies aiming to reactivate the maternal locus and restore the expression of that critical gene cluster. Early therapeutic efforts explored broad-spectrum epigenetic drugs, such as DNA- and histone-methyltransferase inhibitors. While these compounds demonstrated some efficacy in preclinical models, their lack of genomic specificity limits their clinical viability. To overcome this barrier, high-precision epigenome editing tools, most notably dCas9-based systems, have emerged as highly promising strategies capable of inducing site-specific demethylation and stable reactivation of the silenced maternal allele. However, translating these targeted strategies into clinical practice requires overcoming major therapeutic hurdles. This review discusses these key translational challenges, focusing on the imperative to optimize delivery vectors for widespread central nervous system distribution, the necessity of advanced human-derived neuronal models to validate functional recovery, and the critical need to prevent iatrogenic Angelman Syndrome caused by UBE3A imprinting. Finally, we explore future therapeutic horizons, highlighting how newly identified epigenetic regulators and non-coding RNAs could serve as alternative targets to unlock the maternal PWS locus.