PrP-targeting siRNA Safety & Mechanism Study

Purpose

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

Condition

  • Prion Disease

Eligibility

Eligible Ages
Over 18 Years
Eligible Sex
All
Accepts Healthy Volunteers
No

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.

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.

Study Design

Phase
Phase 1
Study Type
Interventional
Allocation
Non-Randomized
Intervention Model
Sequential Assignment
Intervention Model Description
Single ascending dose
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
No Intervention
Arm 1: Observational 		In Arm 1, participants will undergo lumbar punctures and other study activities at baseline (Week 0) and at Week 4 and Week 8. Investigational drug will not be administered. We will prioritize enrollment in Arm 2; Arm 1 will be open to enrollment whenever Arm 2 is not open to enrollment.
Experimental
Arm 2: Single ascending dose 		In Arm 2, participants will be admitted to the clinical trial center and receive a single intrathecal dose of PrP-siRNA. Dose levels to be sequentially evaluated are 50, 100, and 200 mg. Patients will be discharged on Day 2 and then periodically return to the study center on an outpatient basis at Week 1, 2, 4, 8, 12 and 24 for safety monitoring and study activities through the 24 week follow up period.
  • Drug: PrP-siRNA
    Intrathecally administered divalent siRNA designed to target the PRNP mRNA. The structure has been published in DOI: 10.1101/2024.12.05.627039
    Other names:
    • 2439-s4
    • 2439-exNA
    • divalent siRNA 2439-exNA

Recruiting Locations

Massachusetts General Hospital
Boston, Massachusetts 02114

More Details

Status
Recruiting
Sponsor
Broad Institute of MIT and Harvard

Study Contact

Broad Institute
617 714 7000
priontrials@broadinstitute.org

Detailed Description

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.