20.109(S09) TR-yellow Mod3-proposal

Idea

• Do a time course analysis of human diseases, see if knockdown of expression of just one protein can be used to treat multiple prion diseases.
• Treat the whole brain (ie global treatment instead of local treatment)

04/21/2009 Meeting minutes

Experimental steps:

1. pick prion disease (eg. mad cow) 2. knockdown expression of normal protein in (bovinized) mice, see if essential 3. expose to knockdown mice to prion pathogen

Our next steps:

1. research mad cow disease a. mechanism b. how it comes up as a disease c. to what it binds, etc

Papers to discuss next time

1. Kong, Q. RNAi: a novel strategy for the treatment of prion diseases. J Clin Invest. 2006 Dec;116(12):3101-3.
2. Pfiefer et al. Lentivector-mediated RNAi efficiently suppresses prion protein and prolongs survival of scrapie-infected mice. J Clin Invest. 2006 Dec;116(12):3204-10
3. Mallucci et al. Targeting cellular prion protein reverses early cognitive deficits and neurophysiological dysfunction in prion-infected mice. Neuron. 2007 Feb 1;53(3):325-35.
4. Sutou et al. Knockdown of the bovine prion gene PRNP by RNA interference (RNAi) technology. BMC Biotechnol. 2007 Jul 26;7:44.
5. Meslin et al. Silencing of prion protein sensitizes breast adriamycin-resistant carcinoma cells to TRAIL-mediated cell death. Cancer Res. 2007 Nov 15;67(22):10910-9.
6. White 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 U S A. 2008 Jul 22;105(29):10238-43. Epub 2008 Jul 16.

Possible experiments

• want to see if all human prion diseases (which are various mutations in PrnP) can be cured via knockdown of PrnP^C with siRNA
  • Creuztfeldt-Jakob Disease (CJD)
  • FFI (Fatal Familial Insomnia)
  • Kuru
  • Gertsmann-Straussler-Scheinker syndrome (GSS)

Most relevant papers

• Single treatment with RNAi against prion protein rescues early neuronal dysfunction and prolongs survival in mice with prion disease.
  • This paper pretty much paves the way for our work
  • Summary: Treated prion-infected mice with lentiviral siRNA which was injected into the brain. Lentiviral treated mice lived longer than untreated ones.
• Lentivector-mediated RNAi efficiently suppresses prion protein and prolongs survival of scrapie-infected mice.
  • This paper was the first to successfully do lentivector-mediated RNAi treatment in prion-infected mice
  • Summary: infected cells with scrapie, created chimeric mice. Treated those with siRNA that was injected into the striatum.