Despite recent progress that has defined their genetic basis, many inherited neurological diseases remain untreatable and ultimately fatal. In particular, disorders caused by dominant mutations, including Huntington's disease (HD), familial Alzheimer's disease (AD) and DYT1 dystonia (DYT1), progress inexorably due to the toxic or dominant-negative actions of the encoded disease proteins. RNA interference RNAi) has recently emerged as a powerful tool by which to suppress specific genes. In vitro work has now established that dominant disease genes (including those in HD, AD and DYT1) can be silenced by RNAi, in some cases in an allele-specific manner that suppresses only the disease allele. It is unknown, however, whether this technology can work in the mammalian brain to prevent or cure such diseases. The projects in this program address this important question, building on recent advances in RNAi technology and viral-mediated gene transfer to the brain. Project 1 explores the potential of RNAi to prevent or reverse neuropathology in mouse models of HD, one of at least nine neurodegenerative diseases caused by expanded polyglutamine. Project 2 tests whether two genes central to the pathogenesis of familial and sporadic AD can be suppressed by RNAi. Studies will compare the utility of silencing BACE, APP, or both genes, in preventing the development of pathological features in mouse models of AD. Project 3 takes advantage of new cellular and mouse models of DYT1 to test allele-specific silencing of DYT1, and to address new theories about the pathogenic mechanisms of this disease. The PPG benefits from outstanding support by the Vector Core, the Neuropathology Core and the Administrative Core. Together, these studies will provide answers to questions about the efficacy, specificity and longevity of RNAi in the mammalian brain. They will also take us closer to our long-term goal of developing RNAi as therapy for HD, AD, DYT1 and related neurological diseases.
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| Monteys, Alex Mas; Spengler, Ryan M; Dufour, Brett D et al. (2014) Single nucleotide seed modification restores in vivo tolerability of a toxic artificial miRNA sequence in the mouse brain. Nucleic Acids Res 42:13315-27 |
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| Boudreau, Ryan L; Jiang, Peng; Gilmore, Brian L et al. (2014) Transcriptome-wide discovery of microRNA binding sites in human brain. Neuron 81:294-305 |
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| Boudreau, Ryan L; Spengler, Ryan M; Hylock, Ray H et al. (2013) siSPOTR: a tool for designing highly specific and potent siRNAs for human and mouse. Nucleic Acids Res 41:e9 |
| Rodriguez-Lebron, Edgardo; Liu, Gumei; Keiser, Megan et al. (2013) Altered Purkinje cell miRNA expression and SCA1 pathogenesis. Neurobiol Dis 54:456-63 |
| Rodríguez-Lebrón, Edgardo; Costa, Maria do Carmo; Costa, Maria doCarmo et al. (2013) Silencing mutant ATXN3 expression resolves molecular phenotypes in SCA3 transgenic mice. Mol Ther 21:1909-18 |
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