Current genetic approaches for the treatment of prion diseases

Prion diseases are fatal neurodegenerative disorders caused by the misfolding of the host-encoded prion protein (PrP) into a pathogenic conformer (PrP^Sc). Despite decades of investigation, no therapy has proven effective, largely due to rapid disease progression and the absence of druggable intermediates. Recent molecular advances, however, have established PrP itself as a viable therapeutic substrate. Experimental ablation or suppression of Prnp in mice -the gene encoding PrP- confers complete resistance to prion infection in animal models, providing a strong genetic rationale for PrP- lowering interventions. This review focuses on current genetic approaches aiming at reducing PrP expression. Antisense oligonucleotides (ASOs) and RNA-interference (RNAi) vectors have demonstrated potent, durable suppression of Prnp transcripts and extended survival in prion diseases murine models, while genome- and epigenome-editing platforms, including CRISPR-Cas and dCas9-based repressors, now permit permanent or reversible transcriptional control of Prnp with increasing precision. While these technologies are conceptually transformative, translational application faces major challenges, including early diagnosis, brain-wide delivery, biomarker validation and ethical implementation of presymptomatic therapy in Prnp mutation carriers. Integration of validated cerebrospinal biomarkers such as PrP and neurofilament light chain, adaptive trial designs and international registries will be essential for clinical development. Together, these advances position genetic approaches focusing on PrP-lowering as a promising paradigm for preventive treatment of prion diseases and as a model for rational gene-targeted therapies in other rapidly progressive neurodegenerative disorders.