Therapeutic Trajectories in Human Prion Diseases

Prion diseases are rare yet devastating neurodegenerative disorders that result from the misfolding of the cellular prion protein, PrPC, into its infectious and pathogenic isoform, PrPSc. These diseases are marked by progressive neuronal damage, leading to irreversible cognitive and motor impairments and, ultimately, death. Despite extensive research into their underlying mechanisms, effective treatments for prion diseases remain elusive. Such a lack of effective therapies mainly arises from several challenges, including delayed diagnosis and the complex and poorly understood biology of prion neurotoxicity.This chapter provides an in-depth exploration of current and emerging therapeutic strategies to treat prion diseases. One promising approach involves using small molecules to inhibit prion replication by destabilizing PrPSc or modulating PrPC homeostasis, possibly avoiding previously observed strain-dependent drug resistance. In parallel, immunotherapeutic approaches, including passive and active immunization, have shown potential in targeting prions. However, challenges related to brain penetration and potential neurotoxicity remain significant hurdles to their successful clinical application. Developing advanced genetic tools, such as RNA interference (RNAi) and CRISPR-based technologies, has opened up new avenues for therapeutic intervention. These approaches selectively target and reduce PrPC expression, thereby preventing the formation and accumulation of PrPSc. The chapter also highlights the progress in clinical trials, such as the PrProfile trial for ION717, which tests a novel treatment based on an antisense oligonucleotide (ASO). As we look toward the future, the chapter underscores the need for a multifaceted approach to treating prion diseases. Furthermore, early detection methods, innovative drug delivery systems, and collaborative interdisciplinary research efforts will be essential for translating scientific discoveries into practical clinical breakthroughs.