PrPC knockdown by liposome-siRNA-peptide complexes (LSPCs) prolongs survival and normal behavior of prion-infected mice immunotolerant to treatment

Heather Bender, Noelle Noyes, Jessica L. Annis, Amanda Hitpas, Luke Mollnow, Kendra Croak, Sarah Kane, Kaitlyn Wagner, Steven Dow, Mark Zabel

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


Prion diseases are members of neurodegenerative protein misfolding diseases (NPMDs) that include Alzheimer’s, Parkinson’s and Huntington diseases, amyotrophic lateral sclerosis, tauopathies, traumatic brain injuries, and chronic traumatic encephalopathies. No known therapeutics extend survival or improve quality of life of humans afflicted with prion disease. We and others developed a new approach to NPMD therapy based on reducing the amount of the normal, host-encoded protein available as substrate for misfolding into pathologic forms, using RNA interference, a catabolic pathway that decreases levels of mRNA encoding a particular protein. We developed a therapeutic delivery system consisting of small interfering RNA (siRNA) complexed to liposomes and addressed to the central nervous system using a targeting peptide derived from rabies virus glycoprotein. These liposome-siRNA-peptide complexes (LSPCs) cross the blood-brain barrier and deliver PrP siRNA to neuronal cells to decrease expression of the normal cellular prion protein, PrPC, which acts as a substrate for prion replication. Here we show that LSPCs can extend survival and improve behavior of prion-infected mice that remain immunotolerant to treatment. LSPC treatment may be a viable therapy for prion and other NPMDs that can improve the quality of life of patients at terminal disease stages.

Original languageEnglish (US)
Article numbere0219995
JournalPloS one
Issue number7
StatePublished - Jul 1 2019

Bibliographical note

Funding Information:
The National Institutes of Health Institute for Neurological Disorders and Stroke grant R01NS075214 to MZ funded this work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2019 Bender et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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