? ? No treatment exists for any dominantly inherited neurodegenerative disease. In the dominant polyglutamine (polyQ) diseases expansion of a CAG triplet repeat results in a lengthened polyglutamine domain, conferring a dominant toxic property on the gene product. One promising strategy for therapy is therefore reduction of disease protein expression. Recent discoveries coupled with our own preliminary results suggest that small inhibitory RNA (siRNA) may be particularly effective in accomplishing this goal. In this proposal we will use spinocerebellar ataxia type I (SCAl), the best-characterized polyQ disorder, as our principal disease paradigm to test siRNA as a therapeutic approach. Neurodegeneration in SCAl is caused by CAG-repeat expansion in ataxin-1. Here, we will test the effect of siRNA in culture and animal models of SCA-1, which are perfectly suited to test the general therapeutic utility of this approach.
| Ramachandran, Pavitra S; Boudreau, Ryan L; Schaefer, Kellie A et al. (2014) Nonallele specific silencing of ataxin-7 improves disease phenotypes in a mouse model of SCA7. Mol Ther 22:1635-42 |
| Keiser, Megan S; Boudreau, Ryan L; Davidson, Beverly L (2014) Broad therapeutic benefit after RNAi expression vector delivery to deep cerebellar nuclei: implications for spinocerebellar ataxia type 1 therapy. Mol Ther 22:588-595 |
| Ramachandran, Pavitra S; Bhattarai, Sajag; Singh, Pratibha et al. (2014) RNA interference-based therapy for spinocerebellar ataxia type 7 retinal degeneration. PLoS One 9:e95362 |
| Ramachandran, Pavitra S; Keiser, Megan S; Davidson, Beverly L (2013) Recent advances in RNA interference therapeutics for CNS diseases. Neurotherapeutics 10:473-85 |
| Keiser, Megan S; Geoghegan, James C; Boudreau, Ryan L et al. (2013) RNAi or overexpression: alternative therapies for Spinocerebellar Ataxia Type 1. Neurobiol Dis 56:6-13 |
| Rodriguez-Lebron, Edgardo; Liu, Gumei; Keiser, Megan et al. (2013) Altered Purkinje cell miRNA expression and SCA1 pathogenesis. Neurobiol Dis 54:456-63 |
| Boudreau, Ryan L; Rodríguez-Lebrón, Edgardo; Davidson, Beverly L (2011) RNAi medicine for the brain: progresses and challenges. Hum Mol Genet 20:R21-7 |
| Monteys, Alex Mas; Spengler, Ryan M; Wan, Ji et al. (2010) Structure and activity of putative intronic miRNA promoters. RNA 16:495-505 |
| Boudreau, Ryan L; McBride, Jodi L; Martins, Inês et al. (2009) Nonallele-specific silencing of mutant and wild-type huntingtin demonstrates therapeutic efficacy in Huntington's disease mice. Mol Ther 17:1053-63 |
| Boudreau, Ryan L; Martins, Inês; Davidson, Beverly L (2009) Artificial microRNAs as siRNA shuttles: improved safety as compared to shRNAs in vitro and in vivo. Mol Ther 17:169-75 |
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