Below are some of the most common questions we have been getting about PRiSM (NCT07444580), our clinical trial of PrP-siRNA in prion disease.

Q: Which patients are eligible — genetic or sporadic disease, symptomatic or presymptomatic, and at what stage?

A: Symptomatic patients, regardless of whether the disease is genetic or sporadic, may be eligible for the trial if they meet CDC probable diagnostic criteria and have molecular evidence of prion disease — either a positive CSF RT-QuIC or a positive genetic test for a pathogenic PRNP variant. Symptomatic patients must also be at a relatively early disease stage (MRC score ≥ 15). As of October 2026, the trial has also begun accepting pre-symptomatic patients at genetic risk of prion disease into a separate trial arm. For this pre-symptomatic arm, patients must be asymptomatic and have a genetic variant that causes high lifetime risk. Other eligibility criteria apply and will be assessed through a pre-screening phone call and/or a screening visit with the trial site.

Q: Is there a limit on how long since symptom onset?

A: There is no temporal limit so long as the patient still has an MRC score of 15 or above. This selects for patients whose disease is not too advanced.

Q. Why are patients whose disease is too advanced excluded from this trial?

A. While there are not yet any human data on the effects of PrP-siRNA on prion disease progression, data from animal studies suggest that PrP-lowering treatment is more likely to be effective earlier in disease. Such treatments in animal models have taken weeks to reach their full effect, and have not reversed existing symptoms, but only slowed further progression. As we consider how to best gain insights from the first trial of PrP-siRNA in humans, we are compelled to focus in patients who are likely to retain sufficient quality of life for enough time for the drug to take effect; otherwise, it may be difficult to draw conclusions about the safety and efficacy of the drug.

Q: Are people who live outside the United States eligible at all? Can a patient travel in order to enroll, or is residency required?

A: U.S. residency is not a formal requirement for the PRiSM trial, but in most cases international participation is likely to prove impractical or impossible. Key factors that trial sites will consider when evaluating a participant’s eligibility include:

  • Travel burden — the study involves committing to 8 in-person visits over 24 weeks.
  • A caregiver must accompany at all visits
  • Both caregiver and patient must be proficient in English.
  • The family must have some means of obtaining and affording medical care outside of the study, since only study procedures, and not routine clinical care, are covered by our funding.
  • The patient or next of kin giving consent should understand that this is research and that the therapy is not known to be safe or effective; they should not be participating on the expectation of directly benefitting.

Q: If travel is possible, would the patient and family need to remain in the country, and for how long?

A: Participants must commit to 8 in-person visits over 24 weeks.

Q: What would the family be responsible for — travel, accommodation, care, insurance?

A: Participants and their study partners are eligible for up to $500/pair/visit in travel support; this threshold may be adjusted on a case-by-case basis if flights and hotels experience surge pricing in a particular city, for instance due to a special event. All study procedure costs are covered but participants (either independently or through their insurance) must fund any medical care not directly related to the study.

Q: Who should make contact: the family or the treating physician? To which address?

A: Either party can make contact, though the family is likely a more direct route. Please email priontrials@broadinstitute.org or directly contact the trial site nearest you. To reduce the burden on our site coordinators, please do not contact multiple sites at once.

Q: What information should accompany a first contact?

A: Confirmed diagnosis (including diagnostic test results such as CSF RT-QuIC, MRI, and genetic testing), location, and current clinical status (level of impairment). If the participant does not meet CDC diagnostic criteria for probable prion disease and have a positive RT-QuIC or genetic test, then they will be required to get this before a screening visit can be scheduled.

Q: What happens after that, and roughly how long does a reply take?

A: We aim to reply to emails within 2-3 business days and may ask additional questions or provide contact information for a specific site. Once in contact with a site, the site coordinators will share more information regarding the suitability of a pre-screening phone call. If the pre-screening phone call suggests that a potential participant may be eligible, an in-person screening visit will be scheduled.

Q: In the event that there are no treatment arm slots available at the time a participant contacts the study team, what should they expect next?

A: If there are no treatment arm slots available at a given time, a participant may be offered a slot in the observational arm of the trial. While we would like to be able to offer slots in the treatment arm immediately to every eligible participant, this is a very early stage first-in-human trial, which means that long periods of time are taken up by safety review periods before we are permitted to proceed with dosing. In lieu of having a placebo arm, asking participants to volunteer for the observational arm allows us to continue gathering valuable data even while we wait for these safety review periods to pass.

Q: What should participants expect if they enroll in the observational arm?

A: Participants in the observational arm are expected to participate in 4 in-person visits over the course of 8 weeks. The data from this observational arm will help us to measure how biomarkers may change, and how disease may progress, in the absence of treatment. Participants may have the opportunity to cross over to the treatment arm of the trial, if a slot opens up and if they still meet all inclusion criteria at that time, including that disease has not become too advanced. We aim to give priority for treatment arm slots to those who have chosen to participate in the observational arm, compared to people who have not participated. Opportunities to cross over to the treatment arm cannot be guaranteed for observational participants, however, because the results of safety reviews cannot be predicted, and because participants could progress too far before a slot becomes open.

Q: Why can inclusion criteria not be adjusted for an individual case, and who would have to approve any change?

A: We do not yet know whether PrP-siRNA is safe or effective, and PRiSM is a first-in-human trial designed to administer a single dose, and determine a dose level suitable for testing in further trials. Safety is the primary outcome of interest. We set these inclusion criteria to increase the likelihood of having the most informative dataset possible. Ideally, this will maximize the speed with which we can translate this work to future trials and help more patients down the line. Additionally, our protocol has been approved by the FDA (our government oversight agency) and the NIH (our funding institution) and all changes must go through several rounds of approval.

Q: Is expanded access or compassionate use available outside the trial? If not, why not?

A: At this time, there is no Expanded Access or Compassionate Use for the drug product in the PRiSM trial. Given that there are no prior human data on this drug, the FDA has informed us that our program is not eligible to open an Expanded Access Program at this time. Remember that this is a first-in-human study; there is currently no evidence that the drug would provide direct benefit.

Q: What happens to participants when the study ends?

A: After the 24-week follow-up visit that concludes the trial, participants or caregivers will be asked to complete an exit survey and to stay in touch with the study team about their health status. We are not currently cleared by FDA to offer participants a second dose of the drug.

Q: If one trial site determines that a participant is ineligible for the study, can another trial site be contacted?

A: No, all trial sites operate with the same inclusion/exclusion criteria. If a patient is deemed ineligible at one study site, they will be deemed ineligible at all study sites.

Q: What can families do if a patient is not eligible — other studies, registries, brain donation, supportive care?

A: Families wishing to contribute to research can participate in TAPCJD and can donate brain tissue to the National Prion Disease Pathology Surveillance Center. We recommend contacting CJD Foundation for further guidance and support.

Q: Where should they look for future trials, and how will new ones be announced?

A: Keep an eye on CureFFI.org, CJDFoundation.org, CJDISA.com.

Q: Is there a single address for questions, and in which languages can they write?

A: priontrials@broadinstitute.org; Participants may write in English or in their native language, though it will be run through Google Translate and replied to in English or via Google Translate.