A phase 1 clinical trial is now enrolling participants for a new drug candidate aimed at slowing the progression of prion disease. This marks the first time the treatment, a small interfering RNA (siRNA) targeting the prion protein, is being tested in humans. Prion diseases are neurodegenerative disorders caused by the accumulation of misfolded prion protein (PrP) in the brain, with no current cures available. The trial, known as the PrP-targeting siRNA Safety & Mechanism Study (PRiSM), will evaluate the drug's safety and tolerability in patients exhibiting symptoms of the disease.
The drug candidate was developed by scientists at the Broad Institute and the University of Massachusetts Chan Medical School. It is designed to bind and degrade RNA molecules that encode the prion protein, thereby reducing the levels of the disease-causing protein in the brain. Prior animal studies have indicated that lowering prion protein levels can delay the onset and progression of the disease.
Eric Minikel, the principal investigator of the trial and codirector of Broad’s Prion Therapeutic Science program, stated, “To finally advance this drug to a human trial is the long-overdue achievement of a longstanding dream.” He emphasized the importance of learning about the drug's safety and activity in humans and the commitment to sharing data and findings publicly.
The siRNA is a divalent form, meaning it consists of two identical siRNAs linked together, which is expected to distribute more effectively in the brain than single siRNAs. The development of this drug has been a collaborative effort since 2019 by Minikel, Sonia Vallabh, and Anastasia Khvorova, who have focused on creating a treatment for prion disease after Vallabh discovered she has the genetic mutation that causes it.
In March 2025, the U.S. Food and Drug Administration (FDA) approved the Investigational New Drug (IND) application for the trial, which is notable as such documents are typically kept confidential. Minikel and Vallabh opted to publish their IND filing publicly to promote transparency.
The FDA's approval follows encouraging results from animal studies, where the divalent siRNA reduced prion protein levels in mice by 49% and increased survival time by 64% after a single dose post-symptom onset. The findings were published in the journal Nucleic Acids Research.
The clinical trial is supported by NeuroNEXT, a program of the National Institute of Neurological Disorders and Stroke (NINDS), which provides funding and infrastructure for the trial, including trial sites and a clinical coordinating center at Mass General Hospital.
Khvorova praised Minikel and Vallabh for their ethical commitment and vision in advancing clinical trials for prion disease, noting their dedication to transparency. The initial phase of the trial will enroll 15 symptomatic patients, each receiving one dose of the siRNA via lumbar puncture, with plans to increase doses for new participants. An observational arm will include 15 additional participants who will not receive treatment. Future plans may include enrolling pre-symptomatic participants, and safety data will be shared as it becomes available.
Vallabh highlighted the need for a learning system in drug development, stating, “We can’t afford to treat each shot on goal as a self-contained unit – everything needs to feed the mission.” This trial is the second initiated by Vallabh and her team, following a previous trial by Ionis Pharmaceuticals for a different drug candidate.
Funding for the drug development has come from National Institutes of Health grants and donations from the prion disease community. The clinical trial is funded by NINDS through the NeuroNEXT program.
For more information about PRiSM, interested parties can visit ClinicalTrials.gov and CureFFI.org. The CJD Foundation is also recommended for patient resources.