PrP-targeting siRNA Safety & Mechanism Study

NCT07444580 | Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: NN112OT2NS138339
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 5

Brief Summary

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

Conditions

Prion Disease

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Frequency of adverse events

  Baseline to week 24

Secondary Outcomes (9)

• CSF PrP concentration

  4 weeks post-dose

• CSF PrP concentration

  8 weeks post-dose

• CSF PrP concentration

  12 weeks post-dose

• CSF PrP concentration

  24 weeks post-dose

• Plasma concentration of PrP-siRNA

  4 hours post-dose

Study Arms (2)

Arm 1: Observational

NO INTERVENTION

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.

Arm 2: Single ascending dose

EXPERIMENTAL

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

Interventions

PrP-siRNA DRUG

Intrathecally administered divalent siRNA designed to target the PRNP mRNA. The structure has been published in DOI: 10.1101/2024.12.05.627039

Also known as: 2439-s4, 2439-exNA, divalent siRNA 2439-exNA

Arm 2: Single ascending dose

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• clinically manifested symptoms of prion disease, in the opinion of the investigator;
• a diagnosis of probable prion disease according to CDC criteria;
• a positive CSF RT-QuIC or PRNP genetic test;
• no more than moderate functional impairment as quantified by an MRC-PDRS score ≥15; and
• availability of a study partner to assist with study procedures.

You may not qualify if:

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

Sponsors & Collaborators

• Broad Institute of MIT and Harvard: lead
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator

Study Sites (5)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

RECRUITING

Mayo Clinic

Rochester, Minnesota, 55905, United States

RECRUITING

Columbia University Medical Center

New York, New York, 10032, United States

RECRUITING

University Hospitals Cleveland Medical Center

Cleveland, Ohio, 44106, United States

RECRUITING

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

RECRUITING

Related Publications (1)

• 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

  BACKGROUND

MeSH Terms

Conditions

Prion Diseases; Insomnia, Fatal Familial; Creutzfeldt-Jakob Syndrome; Gerstmann-Straussler-Scheinker Disease

Condition Hierarchy (Ancestors)

Central Nervous System Infections; Infections; Central Nervous System Diseases; Nervous System Diseases; Neurodegenerative Diseases; Sleep Initiation and Maintenance Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Dementia; Brain Diseases; Neurocognitive Disorders; Mental Disorders; Heredodegenerative Disorders, Nervous System; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Eric V Minikel, PhD

  Broad Institute of MIT and Harvard

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Broad Institute

CONTACT

617 714 7000; priontrials@broadinstitute.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Single ascending dose

Study Record Dates

• First Submitted: February 24, 2026
• First Posted: March 3, 2026
• Study Start: May 15, 2026
• Primary Completion (Estimated): August 14, 2029
• Study Completion (Estimated): August 14, 2029
• Last Updated: June 5, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: No later than August 14, 2030 through indefinitely.
• Access Criteria: Publicly released.

Locations

US (5)