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In vitro  amplification assays, such as real-time quaking-induced conversion (RT-QuIC) are used to detect aggregation activity of misfolded prion protein (PrP) in brain, cerebrospinal fluid (CSF) and urine samples from patients with a prion disease. We believe that the method also has a much broader application spectrum. In the present study, we applied RT-QuIC as a pre-screening test for substances that potentially inhibit the aggregation process of the cellular PrP (PrP C ) to proteinase (PK)-resistant PrP res . We chose doxycycline as the test substance as it has been tested successfully in animal models and proposed in clinical studies as a therapeutic for prion diseases. The RT-QuIC-reaction was seeded with brain tissue or CSF from sCJD patients and doxycycline was then added in different concentrations as well as at different time points. In both experiments, we observed a dose- and time-dependent inhibition of the RT-QuIC seeding response and a decrease of PK resistant PrP res  when doxycycline was added. In contrast, ampicillin or sucrose had no effect on the RT-QuIC seeding response. Our study is the first to apply RT-QuIC as a pre-screening assay for compounds inhibiting the PrP aggregation  in vitro  and confirms that doxycycline is an efficient inhibitor of the PrP aggregation process in RT-QuIC analysis.

Application of an in vitro-amplification assay as a novel pre-screening test for compounds inhibiting the aggregation of prion protein scrapie