PRNP and prion disease: These data provide important clarification on ASO mechanism of action in prion disease, as oligonucleotides have been shown to sequence-independently interact with prion protein in vitro (71), have been shown to reduce prion load in cellulo independent of impact on PrP levels (72,73), and have been shown to modulate prion disease in animals when pre-incubated with prion inoculum prior to injection, or when used to treat a prion disease in peripheral tissues (72).