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PLoS One. 2014 Sep 10;9(9):e107434. doi: 10.1371/journal.pone.0107434. eCollection 2014.

Allele-specific suppression of mutant huntingtin using antisense oligonucleotides: providing a therapeutic option for all Huntington disease patients.

Author information

1
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
2
ISIS Pharmaceuticals, Carlsbad, California, United States of America.
3
Behavioral Neuroscience Program, Department of Psychology, Western Washington University, Bellingham, Washington, United States of America.
4
Center for Advanced Research in Sleep Medicine, Department of Psychiatry, University of Montréal, Montréal, Quebec, Canada.

Abstract

Huntington disease (HD) is an inherited, fatal neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. The mutant protein causes neuronal dysfunction and degeneration resulting in motor dysfunction, cognitive decline, and psychiatric disturbances. Currently, there is no disease altering treatment, and symptomatic therapy has limited benefit. The pathogenesis of HD is complicated and multiple pathways are compromised. Addressing the problem at its genetic root by suppressing mutant huntingtin expression is a promising therapeutic strategy for HD. We have developed and evaluated antisense oligonucleotides (ASOs) targeting single nucleotide polymorphisms that are significantly enriched on HD alleles (HD-SNPs). We describe our structure-activity relationship studies for ASO design and find that adjusting the SNP position within the gap, chemical modifications of the wings, and shortening the unmodified gap are critical for potent, specific, and well tolerated silencing of mutant huntingtin. Finally, we show that using two distinct ASO drugs targeting the two allelic variants of an HD-SNP could provide a therapeutic option for all persons with HD; allele-specifically for roughly half, and non-specifically for the remainder.

PMID:
25207939
PMCID:
PMC4160241
DOI:
10.1371/journal.pone.0107434
[Indexed for MEDLINE]
Free PMC Article

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