PrP-targeting siRNA Safety & Mechanism Study (PRiSM)

May 7, 2026 updated by: Broad Institute of MIT and Harvard

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.

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

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Estimated)

30

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Recruiting
        • Massachusetts General Hospital
        • Principal Investigator:
          • Steven E Arnold, MD
        • Contact:
        • Contact:
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Recruiting
        • Mayo Clinic
        • Contact:
        • Contact:
        • Principal Investigator:
          • Vijay K Ramanan, MD PhD
    • New York
      • New York, New York, United States, 10032
        • Recruiting
        • Columbia University Medical Center
        • Contact:
        • Contact:
        • Principal Investigator:
          • Lawrence Honig, MD PhD
    • Tennessee
      • Nashville, Tennessee, United States, 37232
        • Recruiting
        • Vanderbilt University Medical Center
        • Contact:
        • Contact:
        • Principal Investigator:
          • Amanda Peltier, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Frequency of adverse events
Time Frame: Baseline to week 24
Baseline to week 24

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
CSF PrP concentration
Time Frame: 4 weeks post-dose
Prion protein (PrP) concentration in cerebrospinal fluid (CSF), a pharmacodynamic (PD) biomarker for PrP-siRNA activity
4 weeks post-dose
CSF PrP concentration
Time Frame: 8 weeks post-dose
Prion protein (PrP) concentration in cerebrospinal fluid (CSF), a pharmacodynamic (PD) biomarker for PrP-siRNA activity
8 weeks post-dose
CSF PrP concentration
Time Frame: 12 weeks post-dose
Prion protein (PrP) concentration in cerebrospinal fluid (CSF), a pharmacodynamic (PD) biomarker for PrP-siRNA activity
12 weeks post-dose
CSF PrP concentration
Time Frame: 24 weeks post-dose
Prion protein (PrP) concentration in cerebrospinal fluid (CSF), a pharmacodynamic (PD) biomarker for PrP-siRNA activity
24 weeks post-dose
Plasma concentration of PrP-siRNA
Time Frame: 4 hours post-dose
A pharmacokinetic (PK) measurement of investigational drug concentration in plasma
4 hours post-dose
Plasma concentration of PrP-siRNA
Time Frame: 24 hours post-dose
A pharmacokinetic (PK) measurement of investigational drug concentration in plasma
24 hours post-dose
Plasma concentration of PrP-siRNA
Time Frame: 4 weeks post-dose
A pharmacokinetic (PK) measurement of investigational drug concentration in plasma
4 weeks post-dose
CSF concentration of PrP-siRNA
Time Frame: 4 weeks post-dose
A pharmacokinetic (PK) measurement of investigational drug concentration in cerebrospinal fluid (CSF)
4 weeks post-dose
Change in CSF PrP over time
Time Frame: Baseline to week 24
Baseline to week 24

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Broad Institute of MIT and Harvard

Collaborators

National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

  • Principal Investigator: Eric V Minikel, PhD, Broad Institute of MIT and Harvard

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

  • Gentile JE, Corridon TL, Serack FE, Echeverria D, Kennedy ZE, Gallant-Behm CL, Hassler MR, Kinberger G, Kamath NG, Lian Y, Gross KY, Miller R, DeSouza-Lenz K, Howard M, Guzman K, Chan N, Curtis DT, Fettes K, Lemaitre M, Cappon G, Jackson AL, Yamada K, Alterman JF, Coffey AA, Minikel EV, Khvorova A, Vallabh SM. Divalent siRNA for prion disease. bioRxiv. 2024 Dec 5;2024.12.05.627039. https://doi.org/10.1101/2024.12.05.627039

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

April 1, 2026

Primary Completion (Estimated)

August 14, 2029

Study Completion (Estimated)

August 14, 2029

Study Registration Dates

First Submitted

February 24, 2026

First Submitted That Met QC Criteria

February 27, 2026

First Posted (Actual)

March 3, 2026

Study Record Updates

Last Update Posted (Actual)

May 11, 2026

Last Update Submitted That Met QC Criteria

May 7, 2026

Last Verified

May 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NN112
  • OT2NS138339 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

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.

IPD Sharing Time Frame

No later than August 14, 2030 through indefinitely.

IPD Sharing Access Criteria

Publicly released.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • ANALYTIC_CODE
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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