In vivo evaluation of candidate allele-specific mutant huntingtin gene silencing antisense oligonucleotides
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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In vivo evaluation of candidate allele-specific mutant huntingtin gene silencing antisense oligonucleotides. / Southwell, Amber L; Skotte, Niels H; Kordasiewicz, Holly B; Østergaard, Michael E; Watt, Andrew T; Carroll, Jeffrey B; Doty, Crystal N; Villanueva, Erika B; Petoukhov, Eugenia; Vaid, Kuljeet; Xie, Yuanyun; Freier, Susan M; Swayze, Eric E; Seth, Punit P; Bennett, Clarence Frank; Hayden, Michael R.
I: Molecular Therapy, Bind 22, Nr. 12, 12.2014, s. 2093-106.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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
Y1 - 2014/12
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
VL - 22
SP - 2093
EP - 2106
JO - Molecular Therapy
JF - Molecular Therapy
SN - 1525-0016
IS - 12
ER -
ID: 153451191