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NCT Number: NCT07444580

PrP-targeting siRNA Safety & Mechanism Study

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

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Key information

Conditions

Prion Disease Brain Diseases Central Nervous System Diseases Central Nervous System Infections Congenital, Hereditary, and Neonatal Diseases and Abnormalities Creutzfeldt-Jakob Syndrome Dementia Dyssomnias Genetic Diseases, Inborn Gerstmann-Straussler-Scheinker Disease Heredodegenerative Disorders, Nervous System Infections Insomnia, Fatal Familial Mental Disorders Nervous System Diseases Neurocognitive Disorders Neurodegenerative Diseases Prion Diseases Sleep Disorders, Intrinsic Sleep Initiation and Maintenance Disorders Sleep Wake Disorders

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

Massachusetts General Hospital, Boston, Massachusetts, United States

Loading trial locations.

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Key inclusion criteria:

  • 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.

Key exclusion criteria:

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

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

Treatment and study plan

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

Other names: 2439-s4, 2439-exNA, divalent siRNA 2439-exNA

Primary outcomes

  1. Frequency of adverse events

    Time frame: Baseline to week 24

Secondary outcomes

  1. 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

  2. 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

  3. 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

  4. 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

  5. Plasma concentration of PrP-siRNA

    Time frame: 4 hours post-dose

    A pharmacokinetic (PK) measurement of investigational drug concentration in plasma

  6. Plasma concentration of PrP-siRNA

    Time frame: 24 hours post-dose

    A pharmacokinetic (PK) measurement of investigational drug concentration in plasma

  7. Plasma concentration of PrP-siRNA

    Time frame: 4 weeks post-dose

    A pharmacokinetic (PK) measurement of investigational drug concentration in plasma

  8. CSF concentration of PrP-siRNA

    Time frame: 4 weeks post-dose

    A pharmacokinetic (PK) measurement of investigational drug concentration in cerebrospinal fluid (CSF)

  9. Change in CSF PrP over time

    Time frame: Baseline to week 24

Study contacts

Contact information is provided by the study sponsor or research team.

Broad Institute

CONTACT

[email protected]

617 714 7000

Sponsors and collaborators

Lead sponsor

Broad Institute of MIT and Harvard

Other

Collaborators

  • National Institute of Neurological Disorders and Stroke (NINDS)

Registry information

Official study title

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.

Acronym: PRiSM

Important dates

Study start
2026
Primary completion
2029
Study completion
2029
First posted
Mar 3, 2026
Registry last updated
Jun 5, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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