A Trial of ALN-6457 in Adult Participants With Symptomatic Prion Disease (PrD)

Key Inclusion Criteria: 1. Participant must meet all of the criteria under either: 1. sporadic CJD as described in the protocol or 2. genetic PrD, as described in the protocol 2. Has a Body Mass Index (BMI) \<35 kg/m2 (inclusive) at the screening visit 3. Able to understand and complete trial-related questionnaires at screening Key Exclusion Criteria: 1. Clinically significant cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, psychiatric or neurological disease (excluding prion disease) that, as assessed by the investigator, may confound the results of the trial or pose an additional risk to the participant during trial participation 2. Medical history of brain or spinal disease/injury that would interfere with the Lumbar Puncture (LP) procedure or CSF circulation, as described in the protocol 3. Any contraindications to undergo a brain Magnetic Resonance Imaging (MRI) 4. An established allergy or intolerance to local anesthetics 5. Current history of bleeding diatheses that would increase risk of bleeding upon LP 6. Any malignancy that is progressing or requires active treatment, as described in the protocol 7. Attempted suicide, suicidal ideation with a plan that required hospital admission and/or change in level of care within 12 months prior to screening NOTE: Other Protocol-Defined Inclusion/Exclusion Criteria Apply.