Clinical trial of a prion disease drug candidate begins enrolling participants
It’s the first time the potential treatment, a small interfering RNA targeting the prion protein, is being tested in humans.
Highlights
- The phase 1 trial will enroll 15 patients diagnosed with prion disease who have symptoms of the neurodegenerative disorder.
- The drug candidate is a divalent small interfering RNA (siRNA) molecule designed to cut target RNA, so cells produce less of the disease-causing prion protein.
- The trial will test the safety and dosing of the siRNA, and help determine whether the drug candidate should advance to larger clinical trials.
A new drug candidate designed to slow the progression of prion disease is entering a phase 1 , which will evaluate the potential medicine for safety and tolerability.
Prion diseases are a class of neurodegenerative disorders that are caused by the accumulation of misfolded prion protein (PrP) in the brain. There are currently no cures, and the disease is fatal within months or years after symptoms begin. The new drug candidate, developed by ӳý and University of Massachusetts Chan Medical School scientists, is a small interfering RNA (siRNA) that binds and snips RNA molecules encoding the prion protein, reducing the amount of the disease-causing protein in the brain. Previous research in animals has shown that lowering prion protein levels can delay onset and slow down the disease. The trial, called PrP-targeting siRNA Safety & Mechanism Study (PRiSM), is enrolling patients exhibiting symptoms of the disease.
“To finally advance this drug to a human trial is the long-overdue achievement of a longstanding dream, but it's also the very beginning of learning about this drug's safety and activity in humans,” said Eric Minikel, principal investigator of the trial and codirector of ӳý’s Prion Therapeutic Science program. “I am looking forward to finding out whether this candidate has a future as a drug in our disease, but no matter what the outcome, as sponsor-investigators, we will learn a lot about how to run a clinical trial in prion disease, and we plan to broadly and publicly share our data and findings to benefit all sponsors who want to develop drugs for prion disease.”
The drug candidate is a divalent siRNA: two identical siRNAs that are linked together and designed to distribute more broadly in the brain than single siRNAs. The divalent siRNA was developed at the UMass Chan Medical School by and her lab. Khvorova, Minikel, and Sonia Vallabh, codirector of ӳý’s Prion Therapeutic Science program, have been working together since 2019 on developing an siRNA-based drug to target prion protein mRNA. Vallabh and Minikel, who are wife and husband, have dedicated their lives to creating a cure or treatment for prion disease, after learning in 2011 that Vallabh has the genetic mutation that causes the disease.
In March 2025, the U.S. Food and Drug Administration (FDA) cleared the team’s Investigational New Drug (IND) application to start a clinical trial on this drug candidate — a document that is usually kept private by drug companies. However, Minikel and Vallabh filing publicly, and have committed to sharing new insights openly.
This green light from the FDA — a significant step in the drug development process — follows promising animal data from the Minikel/Vallabh lab. The scientists showed that a divalent siRNA lowered prion protein in mice by 49 percent and resulted in a 64 percent increase in survival time with a single dose after symptom onset. The study is available as a .
The clinical trial is being supported by NeuroNEXT, or Network for Excellence in Neuroscience Clinical Trials, a program of the National Institute of Neurological Disorders and Stroke (NINDS), a part of the National Institutes of Health. NeuroNEXT provides both funding as well as infrastructure to run the trial, including trial sites, a clinical coordinating center housed at Mass General Hospital’s Neurology Department, and a data and statistics center at the University of Iowa.
“Eric and Sonia are visionaries who are not only top-notch scientists, but have enormous ethical conviction. I’m honored to have an opportunity to work with them,” said Khvorova, professor in UMass’s RNA Therapeutics Institute and Program in Molecular Medicine. “Their commitment to transparency is paving a new path for running a clinical trial, so we’re not only advancing therapy for prion disease, it’s advancing the field as a whole.”
The initial phase of the trial will enroll 15 symptomatic patients who will each receive one dose of the siRNA by lumbar puncture, and new patients enrolled over the course of the trial will receive larger doses than patients enrolled earlier. The trial will also have an observational arm consisting of 15 additional participants who will not receive any treatment. Minikel says they hope to add pre-sympomatic participants in the future. They also plan to share safety data as soon as they are able.
“Standard drug development is, for all sorts of reasons, not well set up to be a learning system,” Vallabh said. “But we can’t afford to treat each shot on goal as a self-contained unit – everything needs to feed the mission. I wish the absolute best for this exact molecule, and I also know that however it performs in the clinic, this experience must move us forward. It’s our job to figure out how.”
This is now the second clinical trial that Vallabh and her team at ӳý have helped to enable. The first one, initiated by Ionis Pharmaceuticals, began in 2023 for drug candidate and is ongoing. In their lab, Minikel and Vallabh are pursuing other possible therapeutic approaches for prion disease, including epigenetic and gene editing.
To learn more about PRiSM, visit and , where Minikel shares information for the prion patient and scientific communities. For patient resources, Minikel and Vallabh recommend visiting the .
Funding
The drug development was funded by National Institutes of Health grants and by donations from members of the prion disease community to the ӳý and to . This clinical trial is being funded by the National Institutes of Neurological Disorders and Stroke through the (Grant 3OT2NS138339-01S2).
