Prion diseases, neurodegenerative conditions which affect both humans and animals, are unique in biology in that they manifest as sporadic, genetic and infectious disorders. They have previously described as the subacute spongiform encephalopathies, slow virus diseases and transmissible dementias, and include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, and the human prion diseases, Creutzfeldt-Jacob disease (CJD), Gertsmann-Stršussler-Scheinker disease (GSS), fatal familial insomnia (FFI) and Kuru. Although historically rare in humans (1/1.000.000 per year world-wide), the appearance of a novel human prion disease, variant CJD (vCJD) caused by the same prion strain as that causing BSE in cattle, has raised the possibility that a major epidemic of vCJD will occur within the U.K. and other European countries as a result of dietary or other exposure to BSE prions. These concerns have led to intense efforts to develop effective therapies.

A potential strategy for preventing neuronal damage in prion diseases is knocking down levels of the endogenous prion protein PrPc, so some researchers have created transgenic mice in which PrPc is deleted. Of course, this is an approach that cannot easily be translated to the clinic.

White and co-workers from the Department of Neurodegenerative Disease, Medical Research Council, Prion Unit Institute of Neurology, University College of London, now demonstrate that RNA interference (RNAi) can improve survival and reduce neuronal dysfunction in prion-infected mice (White M. D. et al., Single treatment with RNAi against prion protein rescues early neuronal dysfunction and prolongs survival in mice with prion disease. Proc. Natl Acad. Sci. USA 105, 10238-10243, 2008).

In recent years the potential of RNAi as a therapeutic strategy for knocking down specific disease-related genes has attracted researchers attention, but none before Whiteís group experimented RNAi in prion diseases.

In an animal model of prion disease mice overexpressing PrPc were inoculated with mouse-adapted prions. More than 50 days after prion infection, a lentivirus expressing short-hairpin RNA (shRNA) that targets PrPc for RNAi was injected into both hippocampi. Control mice was treated with an empty lentiviral vector or remained untreated at all.

The RNA protected the mice against the loss of hippocampal functional integrity that was observed in control animals, as demonstrated by behavioural tests and object recognition memory, and confirmed by the virtual absence of the hallmarks of prion neurotoxicity in the hippocampus: spongiosis and cell death.

These findings indicate that RNAi can have a significant therapeutic impact in a mouse model of prion disease and might be a good candidate for a human cure.


BM&L-September 2008