Imagine you’re a detective investigating a complicated case. You know that the key to solving the mystery lies in uncovering the hidden clues. Similarly, scientists have discovered that the key to understanding neurodegenerative diseases lies in detecting proteopathic seeds, the culprits behind the misfolding of host proteins. Seed amplification assays like PMCA and RT-QuIC have revolutionized research and diagnosis of prion diseases, opening doors to studying other neurodegenerative disorders as well. Clinical trials for adult neurodegenerative diseases have faced numerous challenges, but seed amplification assays offer hope for overcoming these obstacles. By accurately identifying the main pathology and co-pathologies, these assays can improve diagnostic accuracy, enabling early intervention and personalized treatment. They also serve as promising biomarkers to measure the effectiveness of new drugs in preclinical and early clinical stages. The future of seed amplification assays in clinical trials holds great potential in unraveling the mysteries behind neurodegenerative diseases and developing targeted therapies. If you’re intrigued by this groundbreaking research, dive into the underlying study for more fascinating insights!

Prion-like seeded misfolding of host proteins is the leading hypothesised cause of neurodegenerative diseases. The exploitation of the mechanism in the protein misfolding cyclic amplification (PMCA) and real-time quaking-induced conversion (RT-QuIC) assays have transformed prion disease research and diagnosis and have steadily become more widely used for research into other neurodegenerative disorders. Clinical trials in adult neurodegenerative diseases have been expensive, slow, and disappointing in terms of clinical benefits. There are various possible factors contributing to the failure to identify disease-modifying treatments for adult neurodegenerative diseases, some of which include: limited accuracy of antemortem clinical diagnosis resulting in the inclusion of patients with the “incorrect” pathology for the therapeutic; the role of co-pathologies in neurodegeneration rendering treatments targeting one pathology alone ineffective; treatment of the primary neurodegenerative process too late, after irreversible secondary processes of neurodegeneration have become established or neuronal loss is already extensive; and preclinical models used to develop treatments not accurately representing human disease. The use of seed amplification assays in clinical trials offers an opportunity to tackle these problems by sensitively detecting in vivo the proteopathic seeds thought to be central to the biology of neurodegenerative diseases, enabling improved diagnostic accuracy of the main pathology and co-pathologies, and very early intervention, particularly in patients at risk of monogenic forms of neurodegeneration. The possibility of quantifying proteopathic seed load, and its reduction by treatments, is an attractive pharmacodynamic biomarker in the preclinical and early clinical stages of drug development. Here we review some potential applications of seed amplification assays in clinical trials.

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