Prion diseases are among the most devastating and intractable in medicine. Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disorder, progresses from first symptoms to death in a median of just four to six months. There are no treatments. The fundamental problem is not a lack of candidate drugs but a lack of tools to test them: human prions could not be propagated in a dividing cell culture, leaving researchers reliant on slow, expensive mouse bioassays that take months to years to produce results.
That barrier has now fallen. A team at the UK Medical Research Council Prion Unit at University College London has developed a scalable, dividing cell line, called EKV cells, that robustly propagates infectious sCJD prions and quantifies them with sensitivity comparable to gold-standard mouse assays. The work was published June 30 in PNAS.
“This is the tool we have been waiting for,” said Akin Nihat, the study’s first author and an MRC Clinical Research Training Fellow at UCL. “For the first time, we have a renewable, high-throughput platform for understanding human prion propagation and screening drugs.”
The EKV breakthrough
The key advance is the EKV cell line itself. Prior attempts to propagate human prions in dividing cells had failed because the cells either could not sustain prion replication or lost the prion strain’s characteristic properties over time. EKV cells, which the team derived from a humanized mouse cell line expressing the human prion protein (PrP), proved capable of indefinite propagation of sCJD prions while maintaining the core strain-specific signature, including the correct glycoform ratio and conformational properties of the disease-associated PrPSc.
The researchers demonstrated that the prions produced in EKV cells are bona fide infectious agents. Cell lysates injected into humanized transgenic mice caused lethal neurodegenerative disease that was clinically and neuropathologically indistinguishable from disease caused by inoculation with sCJD-infected human brain tissue. The strain-specific signature was preserved.
“The cells replicate authentic human prion infectivity,” the authors wrote. “This is not just the protein, it is the whole infectious agent.”
The Human Prion Assay
Building on the EKV platform, the team developed the Human Prion Assay (HPA), a quantitative cell-based infectivity assay. The HPA reduces the experimental timeline from years to weeks while matching the sensitivity of the end-point titration mouse bioassay, the previous gold standard.
This acceleration has immediate implications for drug discovery. Previously, screening a single compound for anti-prion activity required injecting dozens of mice and waiting up to a year for disease to develop, if it developed at all. The low throughput made it impractical to screen large chemical libraries or systematically optimize lead compounds. The HPA changes that calculus: a single researcher can now test hundreds of compounds in a matter of weeks using standard cell culture plates.
To validate the platform for drug discovery, the team showed that established sCJD infection in EKV cells could be cured using an anti-prion protein antibody (ICSM35, supplied by the UCL spin-out D-Gen Ltd.). This demonstrates that the system can distinguish effective compounds from ineffective ones, a prerequisite for any screening platform.
A bridge to therapy
The broader significance of the work lies in its potential to bridge the critical gap between basic prion biology and therapeutic development. Human prion diseases are caused by the misfolding of the normal prion protein (PrPC) into a pathological form (PrPSc) that recruits and converts additional PrPC molecules, propagating like a chain reaction. Any effective therapy must either block this conversion or clear existing PrPSc. Without a scalable cell model, testing whether a compound accomplishes either goal for human prions was essentially impossible.
“There is a huge unmet need,” said corresponding author Parmjit S. Jat. “Drug discovery has relied on surrogate tools or protracted animal assays, yielding candidates that fail in clinical trials. This platform addresses that directly.”
The team made all cell lines and protocols available to the research community. The work was funded by the UK Medical Research Council and the National Institute for Health Research UCLH Biomedical Research Centre.
Several senior authors, including John Collinge, a director of D-Gen Ltd., which supplied the antibodies used in the validation experiments, have competing financial interests in the commercialization of the technology, as disclosed in the paper. The critical next step will be demonstrating that the HPA can identify compounds that are not only active in cells but also effective in living animals, and, ultimately, in patients.
Source: Nihat, A., Arora, P., Schmidt, C. et al. “A scalable, dividing cell model for the robust propagation and quantification of human sporadic Creutzfeldt–Jakob disease prions.” PNAS 123(27), e2600341123 (2026). DOI: 10.1073/pnas.2600341123