Prion diseases are fatal, transmissible neurodegenerative disorders characterised by accumulation throughout the brain of PrPSc, an abnormally folded isoform of the normal cellular prion protein, PrP. PrPSc is associated with infectivity but is not directly neurotoxic and targeting it is of limited efficacy in prion therapeutics. However, PrP-null mice are resistant to prion infection and neurotoxicity. Transgene-c mediated depletion of neuronal PrP in mice with established prion infection reverses early spongiosis, neuronal loss and cognitive deficits, and prevents clinical disease progression. Thus, reducing PrPC expression in the brain through extrinsic means is likely to be an effective therapy for prion diseases. RNA interference can be exploited to mediate gene silencing and can be stably achieved in non-dividing cells such as neurons by incorporation of the small interfering RNAs into replication-deficient lentiviruses. The work described in this thesis strongly validates the use of lentiviral-mediated RNA interference as a therapeutic approach in prion disease. Reducing PrPc expression with siRNA duplexes enabled clearance of PrPSc and infectivity from prion-infected cells in vitro. Lentiviruses constructed to express the interfering sequences demonstrated effective reduction of PrPc expression in vitro. Stable expression of the interfering RNA molecules in vivo through lentiviral transduction of the hippocampus reduced local pathology and significantly prolonged survival in a mouse model of prion disease. This represents an important and novel advance in the treatment of established prion disease with relevance for all prion strains.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:445325 |
| Date | January 2008 |
| Creators | White, Melanie Denise |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1445182/ |
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