Antisense oligonucleotides extend survival of prion-infected mice

JCI Insight
Gregory J RaymondSonia M Vallabh

Abstract

Prion disease is a fatal, incurable neurodegenerative disease of humans and other mammals caused by conversion of cellular prion protein (PrP; PrPC) into a self-propagating neurotoxic conformer (prions; PrPSc). Strong genetic proofs of concept support lowering PrP expression as a therapeutic strategy. Antisense oligonucleotides (ASOs) can provide a practical route to lowering one target mRNA in the brain, but their development for prion disease has been hindered by three unresolved questions from prior work: uncertainty about mechanism of action, unclear potential for efficacy against established prion infection, and poor tolerability of drug delivery by osmotic pumps. Here we test antisense oligonucleotides (ASOs) delivered by bolus intracerebroventricular injection to intracerebrally prion-infected wild-type mice. Prophylactic treatments given every 2-3 months extended survival times 61-98%, and a single injection at 120 days post-infection, near the onset of clinical signs, extended survival 55% (87 days). In contrast, a non-targeting control ASO was ineffective. Thus, PrP lowering is the mechanism of action of ASOs effective against prion disease in vivo, and infrequent, or even single, bolus injections of ASOs can slow pri...Continue Reading

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Citations

Nov 7, 2019·Nature Biotechnology·Malorye Allison Branca
Sep 29, 2019·Molecular & Cellular Proteomics : MCP·Eric Vallabh MinikelSteven A Carr
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Methods Mentioned

BETA
reverse transcription PCR
electrophoresis

Software Mentioned

ImageScope
GraphPad Prism
R
Aperio Imagescope
ImageQuant

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