Allele-specific suppression of mutant huntingtin using antisense oligonucleotides: providing a therapeutic option for all Huntington disease patients
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Allele-specific suppression of mutant huntingtin using antisense oligonucleotides : providing a therapeutic option for all Huntington disease patients. / Skotte, Niels H; Southwell, Amber L; Østergaard, Michael E; Carroll, Jeffrey B; Warby, Simon C; Doty, Crystal N; Petoukhov, Eugenia; Vaid, Kuljeet; Kordasiewicz, Holly; Watt, Andrew T; Freier, Susan M; Hung, Gene; Seth, Punit P; Bennett, C Frank; Swayze, Eric E; Hayden, Michael R.
In: PLOS ONE, Vol. 9, No. 9, 2014, p. e107434.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Allele-specific suppression of mutant huntingtin using antisense oligonucleotides
T2 - providing a therapeutic option for all Huntington disease patients
AU - Skotte, Niels H
AU - Southwell, Amber L
AU - Østergaard, Michael E
AU - Carroll, Jeffrey B
AU - Warby, Simon C
AU - Doty, Crystal N
AU - Petoukhov, Eugenia
AU - Vaid, Kuljeet
AU - Kordasiewicz, Holly
AU - Watt, Andrew T
AU - Freier, Susan M
AU - Hung, Gene
AU - Seth, Punit P
AU - Bennett, C Frank
AU - Swayze, Eric E
AU - Hayden, Michael R
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
U2 - 10.1371/journal.pone.0107434
DO - 10.1371/journal.pone.0107434
M3 - Journal article
C2 - 25207939
VL - 9
SP - e107434
JO - PLoS ONE
JF - PLoS ONE
SN - 1932-6203
IS - 9
ER -
ID: 153451149