Prion protein lowering is a disease-modifying therapy across prion disease stages, strains and endpoints

Eric Vallabh Minikel, Hien T. Zhao, Jason Le, Jill O'Moore, Rose Pitstick, Samantha Graffam, George A. Carlson, Michael P. Kavanaugh, Jasna Kriz, Jae Beom Kim, Jiyan Ma, Holger Wille, Judd Aiken, Deborah McKenzie, Katsumi Doh-Ura, Matthew Beck, Rhonda O'Keefe, Jacquelyn Stathopoulos, Tyler Caron, Stuart L. SchreiberJeffrey B. Carroll, Holly B. Kordasiewicz, Deborah E. Cabin, Sonia M. Vallabh

Research output: Contribution to journalArticlepeer-review

57 Scopus citations


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 <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.

Original languageEnglish
Pages (from-to)10615-10631
Number of pages17
JournalNucleic Acids Research
Issue number19
StatePublished - Nov 4 2020


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