The purpose of this trial is to evaluate safety, tolerability, pharmacokinetics and pharmacodynamic impact of PrP-siRNA in symptomatic prion disease patients.

This is a first-in-human, open label, single ascending dose study in participants with prion disease. The study will consist of a screening period of up to 2 weeks, administration of a single intrathecal dose of PrP-siRNA, and a 24-week follow-up period. Multiple dose levels will be tested. This trial also includes an observational arm in which participants will not receive investigational drug, and will be followed for an 8-week period after baseline.

Key inclusion criteria:

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; and
5. availability of a study partner to assist with study procedures.

Key exclusion criteria:

1. pregnancy;
2. contraindication to LP; or
3. recent participation in a different prion disease clinical trial.

Additional inclusion and exclusion criteria apply and will be evaluated at screening.

The Broad Institute will share de-identified individual participant data, including biomarker and clinical measurements. Access will be via public dataset release at the time of publication of the study results, or no later than 1 year after the end date of the NIH grant supporting this trial, whichever comes first.

No later than August 14, 2030 through indefinitely.

Publicly released.