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Treatment with a non-toxic, self-replicating anti-prion delays or prevents prion disease in vivo

Molecular Psychiatry volume 23, pages 777–788 (2018)Cite this article

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Abstract

Transmissible spongiform encephalopathies (TSEs) are fatal neurological disorders caused by prions, which are composed of a misfolded protein (PrPSc) that self-propagates in the brain of infected individuals by converting the normal prion protein (PrPC) into the pathological isoform. Here, we report a novel experimental strategy for preventing prion disease based on producing a self-replicating, but innocuous PrPSc-like form, termed anti-prion, which can compete with the replication of pathogenic prions. Our results show that a prophylactic inoculation of prion-infected animals with an anti-prion delays the onset of the disease and in some animals completely prevents the development of clinical symptoms and brain damage. The data indicate that a single injection of the anti-prion eliminated ~99% of the infectivity associated to pathogenic prions. Furthermore, this treatment caused significant changes in the profile of regional PrPSc deposition in the brains of animals that were treated, but still succumbed to the disease. Our findings provide new insights for a mechanistic understanding of prion replication and support the concept that prion replication can be separated from toxicity, providing a novel target for therapeutic intervention.

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Acknowledgements

These studies were supported in part by NIH grant P01 AI106705 to CS and by FONDECYT grant 3150054 from CONICYT to RDE.

Author contributions

RDE performed most of the in vitro experiments, designed the in vivo and in vitro experiments and prepared most of the figures. RM performed all the i.c. inoculations, designed the in vivo experiments and participated in lesion profile assessments. LCM purified recombinant PrP, performed part of the biochemical analysis and carried out the experiments of in vitro competition by PMCA. IMG and FM did the histological work and analysis and IMG prepared the histology figures. CS conceived, supervised the work and prepared the final version of the manuscript.

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Author notes

  1. R Diaz-Espinoza

    Present address: 3Current address: Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Avenida Libertador Bernardo O'Higgins 3363, Santiago, Chile.,

  2. F Moda

    Present address: 4Current address: Istituto Neurologico Carlo Besta, Milan, Italy.,

Authors and Affiliations

  1. Department of Neurology, Mitchell Center for Alzheimer’s Disease and Related Brain Disorders, University of Texas Health Science Center, Houston, TX, USA

    R Diaz-Espinoza, R Morales, L Concha-Marambio, I Moreno-Gonzalez, F Moda & C Soto

  2. Department of Biomedicine, Facultad de Medicina, Universidad de Los Andes, Santiago, Chile

    L Concha-Marambio & C Soto

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  1. R Diaz-Espinoza
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Correspondence to C Soto.

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Diaz-Espinoza, R., Morales, R., Concha-Marambio, L. et al. Treatment with a non-toxic, self-replicating anti-prion delays or prevents prion disease in vivo. Mol Psychiatry 23, 777–788 (2018). https://doi.org/10.1038/mp.2017.84

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