RNA INTERFERENCE AGAINST PRION DISEASES
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-Sträussler-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
White’s 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.