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

Amber L Southwell; Niels H Skotte; Holly B Kordasiewicz; Michael E Østergaard; Andrew T Watt; Jeffrey B Carroll; Crystal N Doty; Erika B Villanueva; Eugenia Petoukhov; Kuljeet Vaid; Yuanyun Xie; Susan M Freier; Eric E Swayze; Punit P Seth; Clarence Frank Bennett; Michael R Hayden

doi:10.1038/mt.2014.153

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

Amber L Southwell, Niels H Skotte, Holly B Kordasiewicz, Michael E Østergaard, Andrew T Watt, Jeffrey B Carroll, Crystal N Doty, Erika B Villanueva, Eugenia Petoukhov, Kuljeet Vaid, Yuanyun Xie, Susan M Freier, Eric E Swayze, Punit P Seth, Clarence Frank Bennett, Michael R Hayden

82 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Molecular Therapy
Vol/bind	22
Udgave nummer	12
Sider (fra-til)	2093-106
Antal sider	14
ISSN	1525-0016
DOI	https://doi.org/10.1038/mt.2014.153
Status	Udgivet - 11 dec. 2014
Udgivet eksternt	Ja

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10.1038/mt.2014.153

http://www.cell.com/article/S152500161630257X/pdfLicens: CC BY-NC-ND

Citationsformater

Southwell, A. L., Skotte, N. H., Kordasiewicz, H. B., Østergaard, M. E., Watt, A. T., Carroll, J. B., Doty, C. N., Villanueva, E. B., Petoukhov, E., Vaid, K., Xie, Y., Freier, S. M., Swayze, E. E., Seth, P. P., Bennett, C. F., & Hayden, M. R. (2014). In vivo evaluation of candidate allele-specific mutant huntingtin gene silencing antisense oligonucleotides. Molecular Therapy, 22(12), 2093-106. https://doi.org/10.1038/mt.2014.153

Southwell, AL, Skotte, NH, Kordasiewicz, HB, Østergaard, ME, Watt, AT, Carroll, JB, Doty, CN, Villanueva, EB, Petoukhov, E, Vaid, K, Xie, Y, Freier, SM, Swayze, EE, Seth, PP, Bennett, CF & Hayden, MR 2014, 'In vivo evaluation of candidate allele-specific mutant huntingtin gene silencing antisense oligonucleotides', Molecular Therapy, bind 22, nr. 12, s. 2093-106. https://doi.org/10.1038/mt.2014.153

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title = "In vivo evaluation of candidate allele-specific mutant huntingtin gene silencing antisense oligonucleotides",

abstract = "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.",

keywords = "Animals, Brain, Disease Models, Animal, Gene Silencing, Humans, Huntington Disease, Injections, Mice, Mice, Inbred C57BL, Molecular Targeted Therapy, Mutant Proteins, Nerve Tissue Proteins, Oligonucleotides, Antisense, Polymorphism, Single Nucleotide, Rats, Rats, Sprague-Dawley, Thionucleotides",

author = "Southwell, {Amber L} and Skotte, {Niels H} and Kordasiewicz, {Holly B} and {\O}stergaard, {Michael E} and Watt, {Andrew T} and Carroll, {Jeffrey B} and Doty, {Crystal N} and Villanueva, {Erika B} and Eugenia Petoukhov and Kuljeet Vaid and Yuanyun Xie and Freier, {Susan M} and Swayze, {Eric E} and Seth, {Punit P} and Bennett, {Clarence Frank} and Hayden, {Michael R}",

year = "2014",

month = dec,

day = "11",

doi = "10.1038/mt.2014.153",

language = "English",

volume = "22",

pages = "2093--106",

journal = "Molecular Therapy",

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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 -

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

Abstract

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