Antagonizing prions

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Science Translational Medicine  23 Oct 2019:
Vol. 11, Issue 515, eaaz3719
DOI: 10.1126/scitranslmed.aaz3719


Combination therapy may offer a way to slow the progression of prion diseases.

Prion diseases are neurodegenerative, protein-misfolding disorders transmissible from person to person and between species. Prion diseases are easily modeled in mice because of their transmissibility and reproducible disease course. As death occurs in a small but consistent timeframe, therapeutic extension of life can be demonstrated. These diseases are highly refractory to treatment, with few compounds extending life in mice to such an extent they might be considered for human trials. This has prompted researchers to consider new approaches in their search for effective therapeutics.

Many putative therapeutic compounds target the replicating misfolded proteins, the prions. Abdulrahman and colleagues hypothesized that combination therapy could be used to synergistically target different aspects of prion disease. They aimed to target both the prions themselves using cellulose ethers and the autophagy pathways that degrade the prions using a PDK1 inhibitor, AR12, or rapamycin to stimulate autophagic activity. Both types of compounds have shown promising extension of life in mice when administered individually. However, the combination therapy failed to confer any extra advantage; the mice receiving both compounds died at the same time as those receiving the single treatments. On further investigation, the authors found that the cellulose ethers inhibited the autophagic activity of AR12 and rapamycin. As a result, it appears that only the benefits of the cellulose ethers were manifest in the mice.

Although the failure of the combination therapy to act synergistically is disappointing, this study highlights some important aspects of therapeutic regimen design that will have to be considered for future success. As very few drugs for neurodegeneration have shown the promise of extending life, drug-drug interactions are almost a complete unknown, but Abdulrahman et al. have demonstrated the need to investigate these phenomena. With the right combination, their approach still offers hope for an effective additive therapy for extending life during prion disease.

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