Human Genetic Evidence for New Targets in Prion Diseases: Opportunities and Challenges

Human genetics offers a powerful, causally grounded approach to therapeutic target identification in prion diseases. In this chapter, we examine strategies used to discover and evaluate gene candidates, emphasizing the complementary roles of literature-based hypotheses, expression profiling, cellular screening, and in vivo models. Although candidate selection using cellular and transcriptomic systems has yielded limited translational success due to their inability to fully model the human disease, they remain valuable tools for mechanistic validation. Animal models retain key pathological features of prion disease and provide insights into cell-type-specific and non-cell-autonomous mechanisms, particularly involving glial contributions.We focus on the translational implications of human genetic discoveries, notably the validation of PRNP as a therapeutic target supported by both Mendelian and GWAS data and the identification of novel risk loci, including STX6 and GAL3ST1. Functional evaluation of these genes across multiple experimental platforms has highlighted the complexity of moving from genetic association to therapeutic intervention. Distinctions in prion disease initiation versus propagation versus neurotoxicity stages, and the need for cell- and stage-specific models, are key considerations.The chapter concludes by outlining a framework for assessing the relevance for target development, integrating genetic evidence, functional models, and safety data. While PRNP-targeting therapies are now entering clinical trials, further research is needed to delineate mechanisms for other candidates. With advances in multiomic data integration and experimental modeling, genetically guided approaches hold great promise in expanding the therapeutic landscape for these currently untreatable neurodegenerative disorders.