Earlier this year we announced PRiSM, a first-in-human clinical trial of a new drug candidate for prion disease. Today, we are opening up a pre-symptomatic arm of this trial, for people living at high genetic risk of prion disease.

The investigational drug is a divalent siRNA called PrP-siRNA, administered intrathecally — meaning, by a lumbar puncture. The drug is designed to reduce the amount of prion protein (or PrP) the brain produces. We do not yet know if PrP-siRNA is safe or effective in any population. The goal of this clinical trial is to gather the very first human safety data to inform dosing and determine whether PrP-siRNA should advance to larger trials that would evaluate safety as well as efficacy in a larger cohort of patients or at-risk individuals.

Who developed this drug, and who is sponsoring this clinical trial?

PrP-siRNA was developed starting in 2020 as a collaboration between our lab at the Broad Institute and Anastasia Khvorova’s lab at UMass Medical School. The project utilized funding from two National Institutes of Health grants (the IGNITE and URGenT programs) as well as from families and members of our patient community who donated either to Prion Alliance or to the Broad Institute. The official sponsor of this clinical trial is the Broad Institute, and the trial is being paid for by a National Institutes of Health program called NeuroNEXT.

What is PrP-siRNA designed to do?

We described research and development of PrP-siRNA in detail in a publication from our lab [Gentile 2026]. PrP-siRNA is a short interfering RNA (siRNA), and has a sequence of A, C, G, and U letters that is designed to target the RNA molecule in our cells that contains instructions to make PrP. PrP is the normal protein that, in disease, misfolds and becomes a pathogenic prion. We and others have hypothesized that reducing the amount of PrP in the brain will slow the progression of prion disease in symptomatic patients, and could delay or prevent the onset of disease in pre-symptomatic, at-risk people. To achieve this, we have designed PrP-siRNA to such that when it finds its target RNA, the cell cuts the target RNA up and produces less PrP.

This trial is the first time PrP-siRNA has ever been administered to humans. There are not yet any human data to indicate that PrP-siRNA will benefit patients.

What is the goal of the study?

The goal of this trial is to evaluate multiple dose levels of PrP-siRNA in a small number of symptomatic patients and now, also at-risk pre-symptomatic individuals. We will evaluate the safety of the investigational drug at each dose level, as well as measuring PrP in spinal fluid to determine whether the drug appears to be lowering PrP in the brain. We hope that results from this trial will help us to determine whether PrP-siRNA is safe enough to justify testing in a larger number of people and determine whether it does what it was designed to do. Depending on the answers, the results from this trial could help to motivate a larger future clinical trial of this investigational drug.

Who is eligible to participate?

Symptomatic patients may be eligible for this study if you meet all of the following criteria:

  • experiencing symptoms of prion disease
  • have been diagnosed with prion disease by a physician, with either a positive RT-QuIC test or a positive genetic test for a PrP mutation
  • still only mildly or moderately impaired
  • have a caregiver able to accompany you to all study visits
  • 18 years of age or older

Pre-symptomatic at-risk individuals may be eligible for this study if you meet all of the following criteria:

  • neurologically healthy, with no symptoms of prion disease
  • have received a positive predictive genetic test report showing that you carry a PRNP variant causing a high lifetime risk of prion disease
  • 18 years of age or older

Additional criteria apply, and will be evaluated at screening.

What does participation involve?

Participants will be admitted to the hospital overnight, will receive an intrathecal (lumbar puncture) injection of the study drug, and will make in-person follow-up visits to the clinic 1, 2, 4, 8, 12, and 24 weeks afterwards. Some follow-up visits will include additional lumbar punctures, MRI scans, blood draws, and cognitive testing.

At certain times, for example while awaiting data that would permit us to escalate to a new dose level, we may be unable to enroll patients in the drug treatment study. Symptomatic patients who approach a study site for screening during one of these times may be offered the option to enroll in an observational arm of the study. Participants in the observational arm will not receive PrP-siRNA, but will make an in-person baseline visit as well as follow-up visits 4 and 8 weeks afterwards. The data from the observational arm will help us to determine whether the drug is having an effect in the treatment arm. If, while you are participating in the observational arm, enrollment in the treatment arm is re-started, you may be offered an opportunity to switch to the treatment arm, but this cannot be guaranteed. The pre-symptomatic arm of the study does not have an observational arm, because we already have a lot of observational data on pre-symptomatic people from our long-running biomarker study at Mass General, now known as OBSERVE.

Who should I contact to learn more or volunteer?

You can read additional details of this trial on its ClinicalTrials.gov posting. If you wish to be screened for possible enrollment, you can reach out to the study site nearest you, or you can contact priontrials@broadinstitute.org