NR AXYR
AU White,M.; Farmer,M.; Brandner,S.; Collinge,J.; Mallucci,G.
TI Single Treatment with RNAi against PrP is Neuroprotective and Prolongs Survival in Prion Diseased Mice
QU International Conference - Prion 2007 (26.-28.9.2007) Edinburgh International Conference Centre, Edinburgh, Scotland, UK - Book of Abstracts: Pathology and Pathogenesis P03.61
IA http://www.prion2007.com/pdf/Prion Book of Abstracts.pdf
PT Konferenz-Poster
AB
Background: We previously showed that knockout of adult neuronal PrPc expression during neuroinvasive disease in mice reversed early pathology and behavioural changes and resulted in long-term survival1,2 validating therapeutic approaches based on targeting host PrPc. However, PrPc depletion in this model was achieved by germline genetic modification. Treatments achieving PrP depletion in vivo may be useful therapeutic approaches in prion disease.
Aims: To achieve therapeutic PrP knockdown in prion-infected mice using lentivirally mediated RNA interference (RNAi) to silence PrPc expression.
Methods: Transgenic mice over-expressing PrP were infected with RML prions intracerebrally. At 8 weeks post inoculation (wpi), when early prion neuropathology was established, we injected a short hairpin (sh)RNA-expressing lentivirus targeting PrP (LV-MW1) into the right hippocampus, and an empty-lentivirus (LV-empty) into the left, and examined the animals neuropathologically two weeks later. We injected further groups of mice bilaterally with either LV-MW1, LV-Empty or with no virus and looked to see the effect of this treatment on prion incubation period.
Results: In prion infected mice injected with different viruses on each side, LV-MW1 resulted in protection against neuronal loss in the right hippocampus, while the LV-
Empty treated left hippocampus showed advanced neurodegeneration. Further, bilateral hippocampal injection of LV-MW1 significantly prolonged survival, as well preventing hippocampal neurodegeneration on both sides. LV-MW1-treated mice had a 17% increase in incubation time compared to animals given LV-empty, or no virus, after only a single localised treatment.
Discussion: The data show that RNAi mediated gene silencing can increase survival time in prion disease even after a single administration. This approach can now be extended to study the temporal, quantitative and regional requirements of PrP knockdown needed to achieve effective therapy.
AD M. White, M. Farmer, S. Brandner, J. Collinge, G. Mallucci, Institute of Neurology, MRC Prion Unit, UK
SP englisch
PO Schottland
EA pdf-Datei und Poster (Posterautoren ergänzt um I. Mirabile)