? ? 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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD044093-02
Application #
6643316
Study Section
Special Emphasis Panel (ZNS1-SRB-S (01))
Program Officer
Oster-Granite, Mary Lou
Project Start
2002-08-07
Project End
2007-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
2
Fiscal Year
2003
Total Cost
$221,250
Indirect Cost
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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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