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

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 - 2014/9/1

Y1 - 2014/9/1

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

SN - 1932-6203

VL - 9

SP - e107434

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 9

ER -