This project is focused on the development of RNAi as therapy for HD. We previously demonstrated the ability of RNAi to silence a disease allele in an animal model of a related neurogenetic disease, Spinocerebellar ataxia type 1, resulting in improved behavior and neuropathology. We will now test several specific hypotheses regarding inhibition of mutant htt expression by RNAi: 1) RNAi can protect, and/or reverse, the neuropathology in mouse models of human Huntington's disease. Earlier studies in an HD mouse model with an inducible mutant allele demonstrate that if expression of the disease allele is abrogated, behavior and pathology improve. RNAi for silencing could yield a similar, promising benefit. 2) RNAi targeted to htt cDNA polymorphisms can be utilized for allele-specific silencing of mutant htt. One published disease-linked polymorphism and several novel ones will be tested for their utility to specifically silence the disease allele in cell culture studies. 3) Regulated RNAi can be achieved in vivo, and can be used to address duration of efficacy. HD usually takes decades to develop. If RNAi is beneficial it is unlikely that lifelong suppression of expression is required for sustained benefit. Thus we will take advantage of our recently developed regulated RNAi vectors to determine how long RNAi-induced improvements last and whether any problems from expressing RNAi in HD brain resolve once vector-expressed RNAi is reduced. 4) The off target effects of RNAi are minimal and can be resolved by cessation of RNAi. Earlier microarray analyses on HD mice brain from various models have shown that transcriptional changes induced by mutant htt are confined to a circumscribed set of genes. Regulatable vectors allow us to test if off-target effects resolve when shRNAs are no longer expressed.
| Lee, John H; Tecedor, Luis; Chen, Yong Hong et al. (2015) Reinstating aberrant mTORC1 activity in Huntington's disease mice improves disease phenotypes. Neuron 85:303-15 |
| 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 |
| 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 |
| 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 |
| Lee, John H; Sowada, Matthew J; Boudreau, Ryan L et al. (2014) Rhes suppression enhances disease phenotypes in Huntington's disease mice. J Huntingtons Dis 3:65-71 |
| 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 |
| Ramachandran, Pavitra S; Keiser, Megan S; Davidson, Beverly L (2013) Recent advances in RNA interference therapeutics for CNS diseases. Neurotherapeutics 10:473-85 |
| 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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