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Prion protein lowering is a disease-modifying therapy across prion disease stages, strains and endpoints
Eric Vallabh Minikel (Broad Institute, Harvard University), Hien Tran Zhao (Ionis Pharmaceuticals (United States)), Jason Le (Broad Institute), Jill O’Moore (McLaughlin Research Institute), Rose Pitstick (McLaughlin Research Institute), Samantha Graffam (Broad Institute), George A. Carlson (McLaughlin Research Institute), Michael P. Kavanaugh (McLaughlin Research Institute), Jasna Križ (Université Laval), Jae Beom Kim, Jiyan Ma (Van Andel Institute), Holger Wille (University of Alberta), Judd M. Aiken (University of Alberta), Deborah McKenzie (University of Alberta), Katsumi Doh‐ura (Tohoku University), Matthew V. Beck (Broad Institute), Rhonda O’Keefe (Broad Institute), Jacquelyn Stathopoulos (Broad Institute), Tyler J. Caron (Broad Institute), Stuart L. Schreiber (Broad Institute, Harvard University), Jeffrey B. Carroll (Western Washington University), Holly B. Kordasiewicz (Ionis Pharmaceuticals (United States)), Deborah E. Cabin (McLaughlin Research Institute), Sonia M. Vallabh (Broad Institute, Harvard University)
Abstract: 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.