Summary
A bioRxiv preprint reports that a cerebrospinal-fluid-delivered siRNA reduced prion protein to 12% residual levels in mouse brain and kept early-treated, prion-infected mice symptom-free through 500 days after inoculation. The researchers also report activity in humanized mice and cynomolgus macaques.
A bioRxiv preprint reports that a small interfering RNA (siRNA) targeting prion protein kept prion-infected mice free of symptoms through 500 days after inoculation when treatment began early and continued chronically. The treatment was delivered into cerebrospinal fluid and reduced brain prion protein to 12% residual levels, the authors say.
Prion diseases involve abnormal forms of prion protein. The study explores whether sharply reducing the supply of the protein can limit disease. Its findings are from animal experiments; the preprint also reports protein lowering in humanized mice and cynomolgus macaques.
Deep lowering was effective across two prion strains
The researchers used a C16-conjugated siRNA, a molecule designed to reduce production of a targeted protein. In mice, the treatment suppressed prion replication by 100-fold and minimized neuropathological changes, according to the abstract.
The work compared the RML and Fukuoka-1 prion strains. The authors report that the strains had indistinguishable prion-replication kinetics, despite differing in their response to more modest, roughly 50% PrP lowering. Deep lowering addressed both strains in the experiments. The researchers suggest that differences in neurotoxicity, rather than replication kinetics, may help explain the strains’ different responses to modest lowering.
The study also treated mice after they had developed symptoms. The authors report a substantial increase in survival and a 10-fold reduction in prion seeding activity—a measure of the capacity of material to initiate prion formation.
Animal findings point to the next translational question
A separate siRNA targeting human PRNP durably lowered PrP in humanized mice and in the brain and cerebrospinal fluid of cynomolgus macaques. These results show activity in additional animal models, but they do not establish clinical benefit or safety in people.
The findings make the degree of protein reduction a central issue: in these experiments, deep lowering was associated with symptom prevention, while the authors describe more variable strain responses to modest lowering. Whether this approach can be used safely and effectively in people with prion disease remains a clinical question.
The report is a bioRxiv preprint. Several authors disclose employment and shareholding at Alnylam Pharmaceuticals or Regeneron Pharmaceuticals, and the paper lists patent interests related to siRNA approaches.