PrP-targeting siRNA safety and mechanism in people with prion disease

An Open-label, Single Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Intrathecally Administered PrP-siRNA in Adult Patients Diagnosed With Symptomatic Prion Disease.

This trial will test whether a single spinal (intrathecal) dose of PrP-targeting siRNA is safe and changes disease-related markers in people with symptomatic prion disease.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 30 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Broad Institute of MIT and Harvard (Academic / other)
• Locations: 4 sites (Boston, Massachusetts and 3 other locations)
• Trial ID: NCT07444580 on ClinicalTrials.gov

What this trial studies

This first-in-human, open-label, single-ascending-dose study gives one intrathecal dose of PrP-siRNA to participants with symptomatic prion disease and follows them for 24 weeks to monitor safety, tolerability, pharmacokinetics, and pharmacodynamic effects. Multiple dose levels will be tested sequentially, with a screening period of up to two weeks prior to dosing. An observational arm will follow participants who do not receive the investigational drug for eight weeks after baseline. Key endpoints include adverse events, CSF and blood drug levels, and biomarkers of PrP biology.

Who should consider this trial

Good fit: Ideal candidates are people with clinically manifested prion disease meeting CDC criteria and confirmed by a positive CSF RT-QuIC or PRNP genetic test, with no more than moderate functional impairment (MRC-PDRS ≥15) and an available study partner.

Not a fit: People who are pregnant, have a contraindication to lumbar puncture, have functional impairment beyond the study limit, or recently participated in another prion trial are unlikely to be eligible or to benefit from this protocol.

Why it matters

Potential benefit: If successful, the treatment could lower pathogenic prion protein levels in the central nervous system and potentially slow or stabilize disease progression.

How similar studies have performed: This is a novel first-in-human approach for prion disease; PrP-lowering strategies have shown benefit in animal models but human data are very limited.

Eligibility criteria

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.

Where this trial is running

Boston, Massachusetts and 3 other locations

• Massachusetts General Hospital — Boston, Massachusetts, United States (Recruiting)
• Mayo Clinic — Rochester, Minnesota, United States (Recruiting)
• Columbia University Medical Center — New York, New York, United States (Recruiting)
• Vanderbilt University Medical Center — Nashville, Tennessee, United States (Recruiting)

Study contacts

• Principal investigator: Eric V Minikel, PhD — Broad Institute of MIT and Harvard
• Study coordinator: Broad Institute

Conditions Prion Disease; prion; Creutzfeldt-Jakob disease; Fatal familial insomnia; Gerstmann-Straussler-Scheinker disease; CJD; FFI; GSS