Prion DiseasePhase 1PRiSMNCT07444580
PrP-targeting siRNA Safety & Mechanism Study
A Phase 1 study testing PrP-siRNA in people with Prion Disease, run by Broad Institute of MIT and Harvard at 5 sites in United States.
Trial summary
The purpose of this trial is to evaluate safety, tolerability, pharmacokinetics and pharmacodynamic impact of PrP-siRNA in symptomatic prion disease patients and in pre-symptomatic adults at genetic risk for prion disease. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Prion Disease
- What is being tested?
- PrP-siRNA
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 45 participants
- Where
- 5 sitesUnited States
- Study dates
- 15 May 2026to 14 Aug 2029
- Phase
- Phase 1
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
- availability of a caregiver to assist with study procedures
- lack of clinically manifested symptoms of prion disease, as demonstrated by an MRC Score of 20, a MoCA score between 24-30 inclusive, and a neurological exam with no clinically significant findings, in the opinion of the investigator
- a PRNP genetic test indicating the presence of a highly penetrant genetic variant causal for prion disease
Who cannot join
- pregnancy or unwillingness to comply with the contraceptive requirements during the study period
- contraindication to lumbar puncture
- recent participation in a different prion disease clinical trial
- Additional inclusion and exclusion criteria apply and will be evaluated at screening.
Trial locations and contacts
5 sites in 1 country. Contact the study team or a site near you to ask about taking part.
5 sites in 1 country
United States5 sites, 5 recruiting
- Recruiting
Massachusetts General Hospital
Boston, Massachusetts, 02114
MGH Prion Studies Coordinator, 617-643-2351, MGHPrionStudy@partners.org
Steven E Arnold, MD
- Recruiting
University Hospitals Cleveland Medical Center
Cleveland, Ohio, 44106
Mary Andrews, BA, RRT, CCRP, 216-844-2386, mary.andrews@uhhospitals.org
Prerna Vatsa, BS, MS, 216-844-2319, prerna.vatsa@uhhospitals.org
- Recruiting
Vanderbilt University Medical Center
Nashville, Tennessee, 37232
Kelly Harper, BPS, 615-322-2538, kelly.a.harper@vumc.org
Leeza Kopaeva, BS, 615-421-4100, leeza.kopaeva@vumc.org
- Recruiting
Columbia University Medical Center
New York, New York, 10032
Katrina Cuasay, BA, 212-305-2077, kc2305@cumc.columbia.edu
Lambrini Whitney, RN, 212-342-5615, lnw2109@cumc.columbia.edu
- Recruiting
Mayo Clinic
Rochester, Minnesota, 55905
Sherry Klingerman, CCRP, 507-284-0451, klingerman.sherry@mayo.edu
Brenda Nelson, 507-293-9237, nelson.brenda6@mayo.edu
About this study
Official title: An Open-label, Single Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Intrathecally Administered PrP-siRNA in Adults Diagnosed With Symptomatic Prion Disease and in Pre-symptomatic Adults at Genetic Risk for Prion Disease.
The purpose of this trial is to evaluate safety, tolerability, pharmacokinetics and pharmacodynamic impact of PrP-siRNA in symptomatic prion disease patients and in pre-symptomatic adults at genetic risk for prion disease.
Read the detailed description
This is a first-in-human, open label, single ascending dose study. 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 symptomatic participants will not receive investigational drug, and will be followed for an 8-week period after baseline.
- Conditions
- Prion Disease
- Being tested
- PrP-siRNA
- Keywords
- prion, Creutzfeldt-Jakob disease, Fatal familial insomnia, Gerstmann-Straussler-Scheinker disease, CJD, FFI, GSS
- Medical subject headings
- Prion Diseases, Insomnia, Fatal Familial, Creutzfeldt-Jakob Syndrome, Gerstmann-Straussler-Scheinker Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PrP-siRNADrug
Also called 2439-s4, 2439-exNA, divalent siRNA 2439-exNA
Intrathecally administered divalent siRNA designed to target the PRNP mRNA. The structure has been published in PMID: 42033217
| Study group | Role | What they receive |
|---|---|---|
| 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: Symptomatic 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. Receives: Drug: PrP-siRNA |
| Arm 3: Pre-symptomatic single ascending dose | Experimental | In Arm 3, 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. Receives: Drug: PrP-siRNA |
What is being measured
The primary outcome is the main question the study is designed to answer.
Frequency of adverse events
Measured: Baseline to week 24
Secondary outcomes (9)
CSF PrP concentration
Prion protein (PrP) concentration in cerebrospinal fluid (CSF), a pharmacodynamic (PD) biomarker for PrP-siRNA activity
Measured: 4 weeks post-dose
CSF PrP concentration
Prion protein (PrP) concentration in cerebrospinal fluid (CSF), a pharmacodynamic (PD) biomarker for PrP-siRNA activity
Measured: 8 weeks post-dose
CSF PrP concentration
Prion protein (PrP) concentration in cerebrospinal fluid (CSF), a pharmacodynamic (PD) biomarker for PrP-siRNA activity
Measured: 12 weeks post-dose
CSF PrP concentration
Prion protein (PrP) concentration in cerebrospinal fluid (CSF), a pharmacodynamic (PD) biomarker for PrP-siRNA activity
Measured: 24 weeks post-dose
Plasma concentration of PrP-siRNA
A pharmacokinetic (PK) measurement of investigational drug concentration in plasma
Measured: 4 hours post-dose
Plasma concentration of PrP-siRNA
A pharmacokinetic (PK) measurement of investigational drug concentration in plasma
Measured: 24 hours post-dose
Plasma concentration of PrP-siRNA
A pharmacokinetic (PK) measurement of investigational drug concentration in plasma
Measured: 4 weeks post-dose
CSF concentration of PrP-siRNA
A pharmacokinetic (PK) measurement of investigational drug concentration in cerebrospinal fluid (CSF)
Measured: 4 weeks post-dose
Change in CSF PrP over time
Measured: Baseline to week 24
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Mar 2026
- Study start15 May 2026
- Primary completion14 Aug 2029 (estimated)
- Study completion14 Aug 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Prion DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Model description
- Single ascending dose
- Masking
- None (open label)
- Enrolment
- 45 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Broad Institute of MIT and Harvard
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute of Neurological Disorders and Stroke (NINDS)
- Responsible party
- Sponsor
- Investigators
- Eric V Minikel, PhD, Principal investigator, Broad Institute of MIT and Harvard
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07444580
- Sponsor's protocol ID
- NN112
- Other IDs
- OT2NS138339
- Acronym
- PRiSM
- Status last verified
- Oct 2026
- First submitted
- 24 Feb 2026
- Last updated
- 16 Oct 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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.
Publications
Gentile JE, Corridon TL, Serack FE, Echeverria D, Kennedy ZC, Gallant-Behm CL, Hassler MR, Kinberger GA, Kelemen MN, Kamath NG, Lian Y, Gross KY, Miller R, DeSouza-Lenz K, Howard M, Guzman K, Chan N, Laversenne V, Curtis D, Fettes K, Lemaitre M, Jackson AL, Yamada K, Alterman JF, Coffey AA, Minikel EV, Khvorova A, Vallabh SM. Divalent siRNA for prion disease. Nucleic Acids Res. 2026 Apr 23;54(8):gkag287. doi: 10.1093/nar/gkag287.
PubMed 42033217
Study at a glance
From the registry record, last updated by the sponsor on 16 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Open-label, Single Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Intrathecally Administered PrP-siRNA in Adults Diagnosed With Symptomatic Prion Disease and in Pre-symptomatic Adults at Genetic Risk for Prion Disease.
- ClinicalTrials.gov ID
- NCT07444580
- Acronym / sponsor ID
- PRiSM / NN112
- Conditions
- Prion Disease
- Keywords
- prion, Creutzfeldt-Jakob disease, Fatal familial insomnia, Gerstmann-Straussler-Scheinker disease, CJD, FFI, GSS
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 45 participants (estimated)
- Lead sponsor
- Broad Institute of MIT and HarvardUniversity, hospital or other
- Collaborators
- National Institute of Neurological Disorders and Stroke (NINDS)
- Study start
- 15 May 2026 (actual)
- Primary completion
- 14 Aug 2029 (estimated)
- Study completion
- 14 Aug 2029 (estimated)
- First posted
- 3 Mar 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this trial is to evaluate safety, tolerability, pharmacokinetics and pharmacodynamic impact of PrP-siRNA in symptomatic prion disease patients and in pre-symptomatic adults at genetic risk for prion disease.
Detailed description
This is a first-in-human, open label, single ascending dose study. 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 symptomatic participants will not receive investigational drug, and will be followed for an 8-week period after baseline.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 3
- Model description
- Single ascending dose
| Arm | Type | Receives |
|---|---|---|
| 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: Symptomatic single ascending dose | Experimental | Drug: PrP-siRNAIn 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. |
| Arm 3: Pre-symptomatic single ascending dose | Experimental | Drug: PrP-siRNAIn Arm 3, 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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
- availability of a caregiver to assist with study procedures
Key exclusion criteria (4 listed)
- pregnancy or unwillingness to comply with the contraceptive requirements during the study period
- contraindication to lumbar puncture
- recent participation in a different prion disease clinical trial
- Additional inclusion and exclusion criteria apply and will be evaluated at screening.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PrP-siRNAAlso: 2439-s4, 2439-exNA, divalent siRNA 2439-exNAIntrathecally administered divalent siRNA designed to target the PRNP mRNA. The structure has been published in PMID: 42033217 | Drug | Arm 2: Symptomatic single ascending dose, Arm 3: Pre-symptomatic single ascending dose |
Primary outcome
Frequency of adverse events
Time frame: Baseline to week 24
9 secondary outcomes
CSF PrP concentration
Time frame: 4 weeks post-dose
CSF PrP concentration
Time frame: 8 weeks post-dose
CSF PrP concentration
Time frame: 12 weeks post-dose
CSF PrP concentration
Time frame: 24 weeks post-dose
Plasma concentration of PrP-siRNA
Time frame: 4 hours post-dose
Plasma concentration of PrP-siRNA
Time frame: 24 hours post-dose
Plasma concentration of PrP-siRNA
Time frame: 4 weeks post-dose
CSF concentration of PrP-siRNA
Time frame: 4 weeks post-dose
Change in CSF PrP over time
Time frame: Baseline to week 24
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Oct 2026.
- Background: PubMed 42033217Gentile JE, Corridon TL, Serack FE, Echeverria D, Kennedy ZC, Gallant-Behm CL, Hassler MR, Kinberger GA, Kelemen MN, Kamath NG, Lian Y, Gross KY, Miller R, DeSouza-Lenz K, Howard M, Guzman K, Chan N, Laversenne V, Curtis D, Fettes K, Lemaitre M, Jackson AL, Yamada K, Alterman JF, Coffey AA, Minikel EV, Khvorova A, Vallabh SM. Divalent siRNA for prion disease. Nucleic Acids Res. 2026 Apr 23;54(8):gkag287. doi: 10.1093/nar/gkag287.
- Individual participant dataSharing planned: Yes. 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Eric V Minikel, PhD principal investigator
Broad Institute of MIT and Harvard
5 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing PrP-siRNA in people with Prion Disease, run by Broad Institute of MIT and Harvard at 5 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 16 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Broad Institute (617 714 7000, priontrials@broadinstitute.org), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Frequency of adverse events (time frame: Baseline to week 24). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07444580, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Oct 2026.