The Generative Brain

PRiSM (NN112)

PRiSM (NN112, NCT07444580) is a Phase 1 first-in-human trial of the divalent siRNA PrP-siRNA given as one lumbar-puncture dose to people with symptomatic prion disease, sponsored by the Broad with NIH NeuroNEXT funding. A pre-symptomatic arm was announced as opening on 14 October 2026. It measures safety, dosing and CSF PrP; it cannot show benefit.

Status as of 2026-10-15. Please check the study registry for the latest position.

Key facts

  • Sponsor Broad Institute; collaborator NINDS; the Broad calls it the official sponsor and NIH NeuroNEXT pays for it.
  • Design: first-in-human, open-label, single ascending dose; screening up to 2 weeks; one intrathecal dose; 24-week follow-up; multiple dose levels (50, 100 and 200 mg on the registry); an observational arm without drug is followed for 8 weeks after baseline.
  • Size and duration: 30 participants and about 175 weeks (aggregator snapshot of 11 May 2026); registry start 2026-05-15 and estimated primary completion 2029-08-14.
  • Symptomatic eligibility: adult; clinical symptoms; probable prion disease by CDC criteria; positive CSF RT-QuIC or PRNP genetic test; MRC Prion Disease Rating Scale score 15 or higher; a study partner. Excluded: pregnancy and contraindication to lumbar puncture.
  • Sites: five US locations per the NeuroNEXT page and registry (MGH, Mayo Rochester, Columbia, Case Western/University Hospitals, Vanderbilt); an aggregator snapshot from May 2026 listed four, so the count has probably risen; check the registry.
  • Sponsor statement (22 April 2026): single dose only, no expanded access, no treatment outside the US because NIH funds US sites; the sponsor does not decide who enrolls; the next stage depends on data, further animal studies and funding for later clinical development. The NPDPSC list shows PRiSM recruiting at US sites with international sites not applicable.
  • Pre-symptomatic arm: age 18 or over, neurologically healthy, positive predictive genetic test report; in July 2026 the Prion Alliance said only symptomatic patients were being recruited and asked the at-risk community to stay tuned.
  • Preclinical basis: mice treated once after symptom onset showed 49 percent PrP lowering and 64 percent longer survival; the study is published in Nucleic Acids Research; drug development was funded by NIH grants and community donations to the Broad and Prion Alliance.
  • The siRNA was developed with the Khvorova lab, from 2019 per the Broad and from 2020 per the Prion Alliance; PRiSM is the second clinical trial the Broad team helped enable (after ION717).

Timeline

  1. 2025IND package posted on the lab page.
  2. 2026Partial clinical hold removal letter (from file name).
  3. 2026Trial launch announced; sponsor community statement.
  4. 2026Mouse study published online (Nucleic Acids Research).
  5. 2026Registry start date.
  6. 2026Prion Alliance mid-year update: symptomatic recruitment only; high interest.
  7. 2026IRB-approved protocol and consent forms posted on the lab page (from file dates).
  8. 2026Pre-symptomatic arm announced as opening.
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