Prevention research

Why is a prevention trial hard to design?

Minikel and colleagues (Neurology 2019) analysed age-at-onset or age-at-death data from 1,094 people with high-penetrance PRNP variants, from 9 study centres, including censored observations. A literature review of 70 reported variants identified 27 likely high-penetrance variants. The main analysis covered 1,001 people with E200K, P102L or D178N, which they report account for about 85 percent of high-penetrance cases in a recent case series. A supplementary table covers 93 people with five-octapeptide-repeat insertions, six-octapeptide-repeat insertions, P105L or A117V.

They report that age at onset varies over several decades for the commonest variants, and that sex, parental age at onset and codon 129 genotype did not add explanatory power for grouping participants in a trial. For E200K, they calculated an annual onset risk of about 5 percent at age 57, so that 20 person-years of follow-up would be expected to produce about one onset. For the three commonest variants, the annual rate stays below 10 percent until after most carriers have died.

From power calculations for randomised trials with onset as the endpoint, they conclude that such a trial would need hundreds or thousands of at-risk people, which would be costly, slow and likely to exceed the pool. They give a rough, conservative estimate of about 60 people in the United States who would meet their criteria. Alternatives they propose are validated biomarkers as surrogate endpoints, longer trials, larger enrolment and historical controls in a post-marketing study. Only about 100,000 of 154,000 characters of the paper were read, so the detailed simulation results are not summarised here.

The authors list as limitations that variant classification relies on literature review, that the US estimate multiplies several approximate proportions, and that privacy prevents a breakdown of predictive test results by age and variant. Penetrance is covered on penetrance.

What is registered for people without symptoms?

The Broad Institute’s PrP-siRNA safety and mechanism study (NCT07444580, 45 participants planned, 5 United States sites, updated 16 October 2026) has a pre-symptomatic arm. As stated by the sponsor on that date, eligibility is no clinically manifest symptoms, an MRC score of 20, a MoCA score of 24 to 30, a neurological examination without clinically significant findings, and a PRNP test showing a highly penetrant causal variant. The primary outcome is the frequency of adverse events to week 24, and CSF PrP is a secondary outcome. The record states no efficacy aim.

The CJD Foundation’s drug development page, citing a statement of 14 October 2026, reports that this pre-symptomatic arm is open. The Prion Alliance’s update of 16 July 2026 had told pre-symptomatic people to wait. Check the registry for current status.

What is not known?

• Whether lowering CSF PrP in carriers delays onset. No registered record reports efficacy data.
• Which biomarker could serve as an accepted surrogate endpoint. See open questions.
• How many eligible carriers could be recruited. The 2019 estimate is for the United States and for specific criteria, and is not an enrolment forecast.

Other resources are on current trials, the research overview, resources, and, for people considering research participation, joining research without testing.