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
(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
encoded from genes that when mutant, cause disease.
our laboratory, we
have tested RNAi strategies for HD, SCA1, SCA6 and SCA7 by creating
RNAs (shRNA) or artificial microRNAs targeting the mRNA encoded by the
disease causing gene. Our laboratory uses adeno-associated virus (AAV)
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
in various cell lines and in vivo
in mouse models of the human diseases. We have also shown improvements
the symptoms in mouse model systems for SCA1 (1) and HD (3, 6).
currently looking at ways to improve on the design, delivery,
expression, and efficacy of these interfering RNAs in vivo.
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)
Generation of hairpin-based RNAi vectors for biological and therapeutic
application. Boudreau RL, Davidson BL. Methods Enzymol.
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)
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
RNAi medicine for the brain: progresses and challenges.
Boudreau RL, Rodríguez-Lebrón E, Davidson BL. Hum Mol Genet. 2011 Apr
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)
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)