On April 22, 2026, the Broad Institute announced that a phase 1 clinical trial has begun enrolling participants to test a novel drug candidate for prion disease. The therapy, known as PrP-targeting siRNA Safety & Mechanism Study (PRiSM), consists of a divalent small interfering RNA (siRNA) molecule designed to bind to and cut the RNA that encodes the prion protein, thereby reducing the production of the disease‑causing protein in the brain. The divalent siRNA was developed by Anastasia Khvorova’s lab at the University of Massachusetts Chan Medical School in collaboration with Broad Institute researchers Sonia Vallabh and Eric Minikel, who co‑direct the Broad’s Prion Therapeutic Science program.
Sonia Vallabh and Eric Minikel co-direct the Broad Institute's Prion Therapeutic Science program and collaborated with Anastasia Khvorova's lab to develop the divalent siRNA drug candidate being tested in the PRiSM clinical trial.
The trial will enroll 15 patients who are already symptomatic with prion disease; each will receive a single dose of the siRNA administered by lumbar puncture, with later participants receiving higher doses to establish safety and tolerability. An additional observational arm of 15 untreated participants will run in parallel for comparison. The study is funded by the National Institute of Neurological Disorders and Stroke through its NeuroNEXT program (Grant 3OT2NS138339-01S2), which provides trial sites, a clinical coordinating center at Massachusetts General Hospital, and a data and statistics center at the University of Iowa. Supplementary support comes from National Institutes of Health grants and donations from the prion disease community to the Broad Institute and the Prion Alliance.
Preclinical work in mice showed that a single dose of the divalent siRNA after symptom onset lowered prion protein levels by 49 % and extended survival time by 64 %, results published in Nucleic Acids Research. However, the approach does not directly clear existing misfolded prion proteins that may already be present in the brain, a limitation noted in discussions about the drug’s mechanism. The investigators plan to share safety data as soon as possible and eventually expand the trial to include presymptomatic participants. This effort marks the second clinical trial enabled by the Vallabh‑Minikel team, following an ongoing trial for the drug candidate ION717 that began in 2023.
The PRiSM trial is testing a divalent siRNA molecule designed to bind to and cut the RNA that encodes the prion protein, thereby reducing production of the disease-causing prion protein in the brain, as described in the article's explanation of the drug's mechanism.