Dominant Neurodegenerative Diease

Genetic diseases that are accompanied by central nervous system involvement are often fatal. Among these are the autosomal dominant neurogenetic diseases caused by nucleotide repeat expansion. For example, Huntington's Disease (HD) and spino-cerebellar ataxia 1 (SCA1) are caused by expansion of a tract of CAGs encoding glutamine. Treatments for these disorders are currently limited to symptomatic intervention. RNA interference (RNAi) is a method for inhibiting target gene expression and provides a unique tool for therapy by attacking the fundamental problem directly.

RNAi is a mechanism by which small inhibitory RNAs can impart repressive activity on gene expression. It is well established that interference of gene expression can occur in plant and mammalian cells either prior to transcription or post-transcriptionally. In my lab we co-opt this naturally occurring system to decrease protein expression of disease causing genes.  In our case, the target cells are cells in the brain and the mRNAs we wish to silence are encoded from genes that when mutant, cause disease.

In our laboratory, we have tested RNAi strategies for HD, SCA1, SCA6 and SCA7 by creating short hairpin RNAs (shRNA) or artificial microRNAs targeting the mRNA encoded by the disease causing gene. Our laboratory uses adeno-associated virus (AAV) as a vehicle to deliver the RNAi therapy into, and expressed in, cells of the brain. We have tested the effectiveness of these RNAi therapies in reducing transcripts in vitro in various cell lines and in vivo in mouse models of the human diseases. We have also shown improvements in the symptoms in mouse model systems for SCA1 (1) and HD (3, 6). We are currently looking at ways to improve on the design, delivery, expression, and efficacy of these interfering RNAs in vivo.
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1. Altered Purkinje cell miRNA expression and SCA1 pathogenesis. Rodriguez-Lebron E, Liu G, Keiser M, Behlke MA, Davidson BL. Neurobiol Dis. 2013 Jan 30. (Abstract)

2. Generation of hairpin-based RNAi vectors for biological and therapeutic application. Boudreau RL, Davidson BL. Methods Enzymol. 2012;507:275-96. (Abstract)

3. Preclinical safety of RNAi-mediated HTT suppression in the rhesus macaque as a potential therapy for Huntington's disease. McBride JL, Pitzer MR, Boudreau RL, Dufour B, Hobbs T, Ojeda SR, Davidson BL. Mol Ther. 2011 Dec;19(12):2152-62. (Abstract)

4. Rational design of therapeutic siRNAs: minimizing off-targeting potential to improve the safety of RNAi therapy for Huntington's disease. Boudreau RL, Spengler RM, Davidson BL. Mol Ther. 2011 Dec;19(12):2169-77. (Abstract)

5. RNAi medicine for the brain: progresses and challenges. Boudreau RL, Rodríguez-Lebrón E, Davidson BL. Hum Mol Genet. 2011 Apr 15;20(R1):R21-7. (Abstract)

6. Nonallele-specific Silencing of Mutant and Wild-type Huntingtin Demonstrates Therapeutic Efficacy in Huntington's Disease Mice. Boudreau RL, McBride JL, Martins I, Shen S, Xing Y, Carter BJ, Davidson BL. Mol Ther. 2009 Jun;17(6):1053-63. (Abstract) (pdf)

7. Artificial miRNAs mitigate shRNA-mediated toxicity in the brain: implications for the therapeutic development of RNAi. McBride JL, Boudreau RL, Harper SQ, Staber PD, Monteys AM, Martins I, Gilmore BL, Burstein H, Peluso RW, Polisky B, Carter BJ, Davidson BL.  Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5868-73. (Abstract)

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