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Lowering of prion protein (PrP) expression in the brain is a genetically validated therapeutic hypothesis in prion disease. We recently showed that antisense oligonucleotide (ASO)-mediated PrP suppression extends survival and delays disease onset in intracerebrally prion-infected mice in both prophylactic and delayed dosing paradigms. Here, we examine the efficacy of this therapeutic approach across diverse paradigms, varying the dose and dosing regimen, prion strain, treatment timepoint, and examining symptomatic, survival, and biomarker readouts. We recapitulate our previous findings with additional PrP-targeting ASOs, and demonstrate therapeutic benefit against four additional prion strains. We demonstrate that less than 25% PrP suppression is sufficient to extend survival and delay symptoms in a prophylactic paradigm. Rise in both neuroinflammation and neuronal injury markers can be reversed by a single dose of PrP-lowering ASO administered after the detection of pathological change. Chronic ASO-mediated suppression of PrP beginning at any time up to early signs of neuropathology confers benefit similar to constitutive heterozygous PrP knockout. Remarkably, even after emergence of frank symptoms including weight loss, a single treatment prolongs survival by months in a subset of animals. These results support ASO-mediated PrP lowering, and PrP-lowering therapeutics in general, as a promising path forward against prion disease. ### Competing Interest Statement SMV has received speaking fees from Illumina and Biogen and has received research support in the form of unrestricted charitable contributions from Charles River Laboratories and Ionis Pharmaceuticals. EVM has received consulting fees from Deerfield Management and Guidepoint and has received research support in the form of unrestricted charitable contributions from Charles River Laboratories and Ionis Pharmaceuticals. HTZ and HBK are employees and shareholders of Ionis Pharmaceuticals. DEC has received research support from Ionis Pharmaceuticals. JBC has received research support from Ionis Pharmaceuticals, Wave Life Sciences, Triplet Therapeutics and consulting fees from Skyhawk Therapeutics and Guidepoint. SLS serves on the Board of Directors of the Genomics Institute of the Novartis Research Foundation (GNF); is a shareholder and serves on the Board of Directors of Jnana Therapeutics; is a shareholder of Forma Therapeutics; is a shareholder and advises Kojin Therapeutics, Kisbee Therapeutics, Decibel Therapeutics and Eikonizo Therapeutics; serves on the Scientific Advisory Boards of Eisai Co., Ltd., Ono Pharma Foundation, Exo Therapeutics, and F-Prime Capital Partners; and is a Novartis Faculty Scholar. Other authors report no conflicts.

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