PrP-targeting siRNA Safety & Mechanism Study

Key inclusion criteria for symptomatic patients: 1. clinically manifested symptoms of prion disease, in the opinion of the investigator 2. a diagnosis of probable prion disease according to CDC criteria 3. a positive CSF RT-QuIC or PRNP genetic test 4. no more than moderate functional impairment as quantified by an MRC-PDRS score ≥15 5. availability of a caregiver to assist with study procedures Key inclusion criteria for pre-symptomatic patients: 1. lack of clinically manifested symptoms of prion disease, as demonstrated by an MRC Score of 20, a MoCA score between 24-30 inclusive, and a neurological exam with no clinically significant findings, in the opinion of the investigator 2. a PRNP genetic test indicating the presence of a highly penetrant genetic variant causal for prion disease Key exclusion criteria for all arms: 1. pregnancy or unwillingness to comply with the contraceptive requirements during the study period 2. contraindication to lumbar puncture 3. recent participation in a different prion disease clinical trial Additional inclusion and exclusion criteria apply and will be evaluated at screening.