The Generative Brain

Pipeline overview

Three PrP-lowering drugs are in registered early trials, and several small-molecule programmes remain in the laboratory, where delivery to the brain is a stated obstacle. No result on efficacy in people has been published for any of them.

Where treatments in development try to step in
  1. The PRNP geneSwitch off or edit the gene that makes the protein.
    • Base editing
    • Epigenetic editing
    • Zinc finger repressors
  2. The RNA messageLower how much protein the cell makes.
    • ION717
    • PrP siRNA
  3. The prion proteinBind the protein or change how cells handle it.
    • PRN100 antibody
    • Small molecules
  4. The brain's responseSupport the cells reacting to the damage.
    • Early ideas

A simplified view: none of these is a proven treatment. ALN-6457 also targets PRNP, but the trial registry does not state its drug type, so it is not placed here.

Where approaches stand
  1. Early research
  2. First human studies
  3. Clinical trials
  4. Approved
Base editing
Epigenetic editing
Zinc finger repressors
Small molecules
PRN100 antibody
ION717 (PrProfile)
PrP siRNA (PRiSM)
ALN-6457

A simplified view. No treatment is proven yet. See the Atlas for each record and its date.

This brief lists what is registered or published, with each programme’s stage as its sponsor or authors describe it. It makes no efficacy claim. For the full list of therapies see the therapy atlas and current trials.

Which drugs are in clinical trials?

Three registered trials test drugs that lower production of prion protein, each given into the spinal fluid space (intrathecally), according to the registry records read on 31 October 2026.

TrialSponsorPhase and statusParticipantsPrimary outcome
PrProfile (ION717), NCT06153966IonisPhase 1/2, active, not recruiting85 (actual)Adverse events to Week 33
PRiSM (PrP-siRNA), NCT07444580Broad Institute, NINDS collaboratingPhase 1, recruiting45 (estimated)Adverse events to Week 24
ALN-6457, NCT07832370RegeneronPhase 1/2, not yet recruiting60 (estimated)Adverse events to Week 156 and change in plasma neurofilament light chain to Week 130

PrProfile has three regimens and a 142-week open-label extension. PRiSM is a single ascending dose study that includes symptomatic adults and pre-symptomatic adults at genetic risk. ALN-6457 is open-label, with dose escalation and expansion cohorts. The endpoints are a comparison of registry designs, not of results. For how endpoints are chosen, see biomarkers and endpoints.

What is in the laboratory?

Laboratory work has found compounds that act in cells but have not yet reached a usable form in animals.

  • Luminescent polythiophenes (Zurich). In 2015 the group reported that its lead compound extended survival in infected mice, by 87.5 percent when given before infection and by 22 percent when given 50 days after infection. The group leader said his lab’s role in developing them as drugs was finished and that pharmaceutical companies would have to take them forward.
  • A SerpinA3n inhibitor (SISSA-led). The 2022 paper reports about 26 percent oral bioavailability in mice, rapid plasma clearance and negligible brain levels. The authors say this did not allow studies in infected mice and that chemistry changes are needed.
  • A zinc porphyrin (iScience 2023). It lowered prion protein in cells. Direct delivery into the brain ventricles gave poor spread into tissue. Treatment for 12 weeks lowered prion protein by roughly 20 percent in mice but did not prolong survival in advanced infection, and the authors call for better pharmacokinetics.

What is unknown?

  • Whether lowering prion protein changes the course of disease in people. The trials above are designed first for safety.
  • Which laboratory compounds will reach the brain at active doses.
  • How many other programmes are unpublished. This list covers only what public sources show.

Next, see regulatory pathway and the pharma hub.

Sources for this page