Creutzfeldt-Jakob disease (CJD): research

What did the completed human studies show?

Seven completed studies, catalogued by cureffi.org, covered the period from about 1997 to 2013. Flupirtine in Germany enrolled 28 people in a randomised double-blind design recruited between 1997 and 2001 and reported slowed cognitive decline on ADAS-Cog at p equal to 0.02, a result that did not become standard care. Pentosan polysulphate was given uncontrolled to 7 people in the United Kingdom between 2003 and 2004, after a court decision made it available, and to 11 in Japan between 2004 and 2007; the first was nominally positive and attributed to a confounder, the second negative. Quinacrine was studied three times: 32 people in France in compassionate use between 2001 and 2002, negative; 107 people in the United Kingdom in PRION-1, an open-label patient-preference design between 2001 and 2006, nominally positive and attributed to a confounder; and 54 people in the United States in a randomised placebo-controlled trial between 2005 and 2009, negative. Doxycycline in France and Italy enrolled 121 people in a randomised double-blind placebo-controlled design between 2007 and 2012 and was negative.

Only symptomatic people took part in all of them, most with sporadic CJD. The cureffi account identifies the shared methodological problem: survival endpoints in these trials are confounded by sex, age, CJD subtype and codon 129 genotype, and stratifying by those factors leaves subgroups too small to analyse. It notes that the doxycycline trial was powered only to detect a two-fold increase in one-year survival, and that the quinacrine lead author described the two-month randomised phase of the United States trial as a design weakness.

What happened in the PRN100 programme?

Mead and colleagues treated six patients with probable CJD at University College London Hospital in 2018 and 2019 with PRN100, a humanised monoclonal antibody against cellular prion protein, under a Specials Licence, which permits a clinician to use an unlicensed medicine for an individual patient. This was a treatment programme with comparison against untreated natural-history controls rather than a randomised trial.

The reported outcomes were that the target cerebrospinal fluid concentration of 50 nM was reached in four of the six patients, that no clinically significant adverse reactions occurred, and that all six patients declined neurologically. Neuropathology in two patients showed no cytotoxicity. One patient survived 140 days, which the authors describe as the longest documented clinical duration for iatrogenic CJD. The authors state that the results justify formal efficacy trials; the paper reports no demonstration of efficacy. The 2026 Viruses review summarises PRN100 as showing acceptable safety and central nervous system penetration without proven efficacy. The CJD Foundation drug development page lists PRN100 as not currently enrolling.

Which programmes are active?

The CJD Foundation drug development page lists several programmes with trial registrations. An Ionis antisense oligonucleotide programme targeting PRNP messenger RNA appears under NCT06153966, with a statement dated 18 September 2026 referring to completed enrolment for one regimen. A Broad Institute divalent siRNA programme appears under NCT07444580, with a presymptomatic arm opened according to a statement dated 14 October 2026. A Regeneron divalent siRNA, ALN-6457, appears under NCT07832370 in adults with symptomatic prion disease. Sangamo zinc finger transcription factors are described as preclinical and not currently enrolling, and a NobelPharma agent as preclinical with clinical studies expected the following year according to remarks from July 2025. All of these statuses are as that page states them. Current registrations are tracked in trials.

Several gene therapy and small molecule approaches sit earlier than that. A 2024 CJD Foundation grant to Qingzhong Kong at Case Western Reserve University and the National Prion Disease Pathology Surveillance Center funds development of an ADAM8-based gene therapy, using an adeno-associated viral vector expressing a prion-protein-cleaving enzyme in a mouse model of CJD. A 2024 grant to Joaquin Castilla at CIC bioGUNE in Derio, Spain, funds an in vivo proof-of-concept study of dominant negative prion protein variants, selected from analyses across mammal species, which can perform normal prion protein functions without misfolding and which would be expressed in the brain from adeno-associated viral vectors. A 2025 grant to Nina Oberbeck at Gate Bioscience funds assessment of a Molecular Gate, a small molecule taken orally that blocks export of prion protein from the cell so that it is degraded instead of secreted; the grant page reports that a lead compound reduced brain prion protein by 80 percent after one week of daily dosing in mice, and that the survival study in a prion disease mouse model is to be run with the Vallabh and Minikel laboratory at the Broad Institute. Oberbeck leads the company’s prion programme and has presented the work at Prion 2024 in Nanchang and at the 14th annual national CJD conference in Melbourne in 2023.

A 2024 grant to Adriano Aguzzi and Davide Caredio at the University of Zurich takes a different direction, raising rather than lowering a protein. It funds a CRISPR activation screen across human microglia to find genes that increase production of GPNMB, followed by testing of candidate genes in models that more closely resemble disease. The grant page states that GPNMB may protect neurons and reduce harmful inflammation but typically rises only at advanced stages, and that adding GPNMB to brain tissue in the laboratory protected it from the effects of prions. That laboratory observation appears on the grant page without data, sample sizes or a published reference. The published work from that group is discussed in sporadic CJD research.

What is known about the decision to be tested?

Schwartz and colleagues studied the people who consulted the genetics department at Pitie-Salpetriere between 2004 and 2017 after learning that a relative carried a pathogenic PRNP variant. Of 30 people who consulted, 20 chose testing, giving 8 carriers and 12 non-carriers, and 10 did not test. Nineteen agreed to take part in interviews with the Beck Depression Inventory and the State-Trait Anxiety Inventory in 2017: 3 of 8 carriers, 10 of 12 non-carriers and 6 of 10 untested.

Anxiety scores above 35 were found in 5 of 6 untested, 7 of 10 non-carriers and 1 of 3 carriers. Depression was reported in 3 of 6 untested and 4 of 9 non-carriers, and in none of the three carriers. Non-carriers described relief together with a remaining burden, guilt and anger about the family’s disease. The authors conclude that psychological strain is present whatever a person decides and whatever the result, that testing did not relieve anxiety about the family disease, and that genetic counselling should address non-carriers and people who chose not to test as well as carriers. Their stated limitations are a very small sample, an exploratory and largely qualitative analysis, no baseline or follow-up measures, and a low response rate among carriers.

The decision belongs with a genetic counsellor, who comes before any test, and not being tested is a valid choice. The national CJD reference unit at Pitie-Salpetriere and the Paris Brain Institute were both involved in that study, and the national prion patient file was used only to establish that the carriers were not recorded as having developed symptoms.

Where does the disease boundary sit?

For OMIM 123400, NCBI MedGen returns inherited Creutzfeldt-Jakob disease, grouped as a genetic prion disease with three major phenotypes: genetic CJD, fatal familial insomnia and Gerstmann-Straussler-Scheinker syndrome. Three further MedGen entries also link to that OMIM number: Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob disease and sporadic Creutzfeldt-Jakob disease. A single identifier therefore covers forms with different causes, which is worth checking when registries or condition lists are compared.

Animal prion disease relevant to the human exposure question is covered in chronic wasting disease, the thalamic phenotype in fatal familial insomnia, and the diagnostic sequence in how prion disease is diagnosed and how it is diagnosed. For what the illness involves day to day, see what to expect. The disease group as a whole is set out in disease research.