Potent and selective antisense oligonucleotides targeting single-nucleotide polymorphisms in the Huntington disease gene / allele-specific silencing of mutant huntingtin

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Potent and selective antisense oligonucleotides targeting single-nucleotide polymorphisms in the Huntington disease gene / allele-specific silencing of mutant huntingtin. / Carroll, Jeffrey B; Warby, Simon C; Southwell, Amber L; Doty, Crystal N; Greenlee, Sarah; Skotte, Niels; Hung, Gene; Bennett, C Frank; Freier, Susan M; Hayden, Michael R.

In: Molecular therapy : the journal of the American Society of Gene Therapy, Vol. 19, No. 12, 12.2011, p. 2178-85.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Carroll, JB, Warby, SC, Southwell, AL, Doty, CN, Greenlee, S, Skotte, N, Hung, G, Bennett, CF, Freier, SM & Hayden, MR 2011, 'Potent and selective antisense oligonucleotides targeting single-nucleotide polymorphisms in the Huntington disease gene / allele-specific silencing of mutant huntingtin', Molecular therapy : the journal of the American Society of Gene Therapy, vol. 19, no. 12, pp. 2178-85. https://doi.org/10.1038/mt.2011.201

APA

Carroll, J. B., Warby, S. C., Southwell, A. L., Doty, C. N., Greenlee, S., Skotte, N., Hung, G., Bennett, C. F., Freier, S. M., & Hayden, M. R. (2011). Potent and selective antisense oligonucleotides targeting single-nucleotide polymorphisms in the Huntington disease gene / allele-specific silencing of mutant huntingtin. Molecular therapy : the journal of the American Society of Gene Therapy, 19(12), 2178-85. https://doi.org/10.1038/mt.2011.201

Vancouver

Carroll JB, Warby SC, Southwell AL, Doty CN, Greenlee S, Skotte N et al. Potent and selective antisense oligonucleotides targeting single-nucleotide polymorphisms in the Huntington disease gene / allele-specific silencing of mutant huntingtin. Molecular therapy : the journal of the American Society of Gene Therapy. 2011 Dec;19(12):2178-85. https://doi.org/10.1038/mt.2011.201

Author

Carroll, Jeffrey B ; Warby, Simon C ; Southwell, Amber L ; Doty, Crystal N ; Greenlee, Sarah ; Skotte, Niels ; Hung, Gene ; Bennett, C Frank ; Freier, Susan M ; Hayden, Michael R. / Potent and selective antisense oligonucleotides targeting single-nucleotide polymorphisms in the Huntington disease gene / allele-specific silencing of mutant huntingtin. In: Molecular therapy : the journal of the American Society of Gene Therapy. 2011 ; Vol. 19, No. 12. pp. 2178-85.

Bibtex

@article{2ff3a7fca2c34597a0f405194ce1fe62,
title = "Potent and selective antisense oligonucleotides targeting single-nucleotide polymorphisms in the Huntington disease gene / allele-specific silencing of mutant huntingtin",
abstract = "Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG-expansion in the huntingtin gene (HTT) that results in a toxic gain of function in the mutant huntingtin protein (mHTT). Reducing the expression of mHTT is therefore an attractive therapy for HD. However, wild-type HTT protein is essential for development and has critical roles in maintaining neuronal health. Therapies for HD that reduce wild-type HTT may therefore generate unintended negative consequences. We have identified single-nucleotide polymorphism (SNP) targets in the human HD population for the disease-specific targeting of the HTT gene. Using primary cells from patients with HD and the transgenic YAC18 and BACHD mouse lines, we developed antisense oligonucleotide (ASO) molecules that potently and selectively silence mHTT at both exonic and intronic SNP sites. Modification of these ASOs with S-constrained-ethyl (cET) motifs significantly improves potency while maintaining allele selectively in vitro. The developed ASO is potent and selective for mHTT in vivo after delivery to the mouse brain. We demonstrate that potent and selective allele-specific knockdown of the mHTT protein can be achieved at therapeutically relevant SNP sites using ASOs in vitro and in vivo.",
keywords = "Alleles, Animals, Brain, Cells, Cultured, Female, Fibroblasts, Gene Silencing, Genetic Therapy, Humans, Huntingtin Protein, Huntington Disease, Male, Mice, Mice, Transgenic, Mutant Proteins, Nerve Tissue Proteins, Neurons, Nuclear Proteins, Oligonucleotides, Antisense, Pedigree, Polymorphism, Single Nucleotide, RNA, Messenger, Serotonin Plasma Membrane Transport Proteins, Trinucleotide Repeat Expansion, Journal Article, Research Support, Non-U.S. Gov't",
author = "Carroll, {Jeffrey B} and Warby, {Simon C} and Southwell, {Amber L} and Doty, {Crystal N} and Sarah Greenlee and Niels Skotte and Gene Hung and Bennett, {C Frank} and Freier, {Susan M} and Hayden, {Michael R}",
year = "2011",
month = dec,
doi = "10.1038/mt.2011.201",
language = "English",
volume = "19",
pages = "2178--85",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "nature publishing group",
number = "12",

}

RIS

TY - JOUR

T1 - Potent and selective antisense oligonucleotides targeting single-nucleotide polymorphisms in the Huntington disease gene / allele-specific silencing of mutant huntingtin

AU - Carroll, Jeffrey B

AU - Warby, Simon C

AU - Southwell, Amber L

AU - Doty, Crystal N

AU - Greenlee, Sarah

AU - Skotte, Niels

AU - Hung, Gene

AU - Bennett, C Frank

AU - Freier, Susan M

AU - Hayden, Michael R

PY - 2011/12

Y1 - 2011/12

N2 - Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG-expansion in the huntingtin gene (HTT) that results in a toxic gain of function in the mutant huntingtin protein (mHTT). Reducing the expression of mHTT is therefore an attractive therapy for HD. However, wild-type HTT protein is essential for development and has critical roles in maintaining neuronal health. Therapies for HD that reduce wild-type HTT may therefore generate unintended negative consequences. We have identified single-nucleotide polymorphism (SNP) targets in the human HD population for the disease-specific targeting of the HTT gene. Using primary cells from patients with HD and the transgenic YAC18 and BACHD mouse lines, we developed antisense oligonucleotide (ASO) molecules that potently and selectively silence mHTT at both exonic and intronic SNP sites. Modification of these ASOs with S-constrained-ethyl (cET) motifs significantly improves potency while maintaining allele selectively in vitro. The developed ASO is potent and selective for mHTT in vivo after delivery to the mouse brain. We demonstrate that potent and selective allele-specific knockdown of the mHTT protein can be achieved at therapeutically relevant SNP sites using ASOs in vitro and in vivo.

AB - Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG-expansion in the huntingtin gene (HTT) that results in a toxic gain of function in the mutant huntingtin protein (mHTT). Reducing the expression of mHTT is therefore an attractive therapy for HD. However, wild-type HTT protein is essential for development and has critical roles in maintaining neuronal health. Therapies for HD that reduce wild-type HTT may therefore generate unintended negative consequences. We have identified single-nucleotide polymorphism (SNP) targets in the human HD population for the disease-specific targeting of the HTT gene. Using primary cells from patients with HD and the transgenic YAC18 and BACHD mouse lines, we developed antisense oligonucleotide (ASO) molecules that potently and selectively silence mHTT at both exonic and intronic SNP sites. Modification of these ASOs with S-constrained-ethyl (cET) motifs significantly improves potency while maintaining allele selectively in vitro. The developed ASO is potent and selective for mHTT in vivo after delivery to the mouse brain. We demonstrate that potent and selective allele-specific knockdown of the mHTT protein can be achieved at therapeutically relevant SNP sites using ASOs in vitro and in vivo.

KW - Alleles

KW - Animals

KW - Brain

KW - Cells, Cultured

KW - Female

KW - Fibroblasts

KW - Gene Silencing

KW - Genetic Therapy

KW - Humans

KW - Huntingtin Protein

KW - Huntington Disease

KW - Male

KW - Mice

KW - Mice, Transgenic

KW - Mutant Proteins

KW - Nerve Tissue Proteins

KW - Neurons

KW - Nuclear Proteins

KW - Oligonucleotides, Antisense

KW - Pedigree

KW - Polymorphism, Single Nucleotide

KW - RNA, Messenger

KW - Serotonin Plasma Membrane Transport Proteins

KW - Trinucleotide Repeat Expansion

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1038/mt.2011.201

DO - 10.1038/mt.2011.201

M3 - Journal article

C2 - 21971427

VL - 19

SP - 2178

EP - 2185

JO - Molecular Therapy

JF - Molecular Therapy

SN - 1525-0016

IS - 12

ER -

ID: 170597568