In vivo evaluation of candidate allele-specific mutant huntingtin gene silencing antisense oligonucleotides

TY - JOUR

T1 - In vivo evaluation of candidate allele-specific mutant huntingtin gene silencing antisense oligonucleotides

AU - Southwell, Amber L

AU - Skotte, Niels H

AU - Kordasiewicz, Holly B

AU - Østergaard, Michael E

AU - Watt, Andrew T

AU - Carroll, Jeffrey B

AU - Doty, Crystal N

AU - Villanueva, Erika B

AU - Petoukhov, Eugenia

AU - Vaid, Kuljeet

AU - Xie, Yuanyun

AU - Freier, Susan M

AU - Swayze, Eric E

AU - Seth, Punit P

AU - Bennett, Clarence Frank

AU - Hayden, Michael R

PY - 2014/12/11

Y1 - 2014/12/11

N2 - Huntington disease (HD) is a dominant, genetic neurodegenerative disease characterized by progressive loss of voluntary motor control, psychiatric disturbance, and cognitive decline, for which there is currently no disease-modifying therapy. HD is caused by the expansion of a CAG tract in the huntingtin (HTT) gene. The mutant HTT protein (muHTT) acquires toxic functions, and there is significant evidence that muHTT lowering would be therapeutically efficacious. However, the wild-type HTT protein (wtHTT) serves vital functions, making allele-specific muHTT lowering strategies potentially safer than nonselective strategies. CAG tract expansion is associated with single nucleotide polymorphisms (SNPs) that can be targeted by gene silencing reagents such as antisense oligonucleotides (ASOs) to accomplish allele-specific muHTT lowering. Here we evaluate ASOs targeted to HD-associated SNPs in acute in vivo studies including screening, distribution, duration of action and dosing, using a humanized mouse model of HD, Hu97/18, that is heterozygous for the targeted SNPs. We have identified four well-tolerated lead ASOs that potently and selectively silence muHTT at a broad range of doses throughout the central nervous system for 16 weeks or more after a single intracerebroventricular (ICV) injection. With further validation, these ASOs could provide a therapeutic option for individuals afflicted with HD.

AB - Huntington disease (HD) is a dominant, genetic neurodegenerative disease characterized by progressive loss of voluntary motor control, psychiatric disturbance, and cognitive decline, for which there is currently no disease-modifying therapy. HD is caused by the expansion of a CAG tract in the huntingtin (HTT) gene. The mutant HTT protein (muHTT) acquires toxic functions, and there is significant evidence that muHTT lowering would be therapeutically efficacious. However, the wild-type HTT protein (wtHTT) serves vital functions, making allele-specific muHTT lowering strategies potentially safer than nonselective strategies. CAG tract expansion is associated with single nucleotide polymorphisms (SNPs) that can be targeted by gene silencing reagents such as antisense oligonucleotides (ASOs) to accomplish allele-specific muHTT lowering. Here we evaluate ASOs targeted to HD-associated SNPs in acute in vivo studies including screening, distribution, duration of action and dosing, using a humanized mouse model of HD, Hu97/18, that is heterozygous for the targeted SNPs. We have identified four well-tolerated lead ASOs that potently and selectively silence muHTT at a broad range of doses throughout the central nervous system for 16 weeks or more after a single intracerebroventricular (ICV) injection. With further validation, these ASOs could provide a therapeutic option for individuals afflicted with HD.

KW - Animals

KW - Brain

KW - Disease Models, Animal

KW - Gene Silencing

KW - Humans

KW - Huntington Disease

KW - Injections

KW - Mice

KW - Mice, Inbred C57BL

KW - Molecular Targeted Therapy

KW - Mutant Proteins

KW - Nerve Tissue Proteins

KW - Oligonucleotides, Antisense

KW - Polymorphism, Single Nucleotide

KW - Rats

KW - Rats, Sprague-Dawley

KW - Thionucleotides

U2 - 10.1038/mt.2014.153

DO - 10.1038/mt.2014.153

M3 - Journal article

C2 - 25101598

SN - 1525-0016

VL - 22

SP - 2093

EP - 2106

JO - Molecular Therapy

JF - Molecular Therapy

IS - 12

ER -