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Pharmacologic lowering of PrP expression is efficacious against prion disease in animal models and is now being tested clinically. 50% lowering of PrP increases both survival time and healthy life in prion-infected mice, but does not prevent symptom onset nor halt disease progression. Additional drug candidates should seek to reduce PrP expression to even lower levels. Divalent siRNA is a novel oligonucleotide drug modality with promising potency, durability, and biodistribution data in preclinical models, inspiring us to seek in this technology a new drug candidate for prion disease. Here, we first identify a tool compound against the mouse PrP gene and establish the efficacy of PrP-lowering divalent siRNA in prion-infected mice. We then introduce humanized transgenic mouse lines harboring the full non-coding sequence of the human PrP gene as tools for identifying human sequence-targeted drugs. We identify a highly potent siRNA sequence against the human PrP gene and determine that a chemical scaffold incorporating extended nucleic acid and a 3′ antisense tail unmatched to the RNA target yields superior potency. We nominate PrP-lowering divalent siRNA 2439-s4 as a new drug candidate for human prion disease.