In Vivo Evaluation of Candidate Allele-specific Mutant Huntingtin Gene Silencing Antisense Oligonucleotides
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 huntin...
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| Veröffentlicht in: | Molecular therapy 2014-12, Vol.22 (12), p.2093-2106 |
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| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1038/mt.2014.153 |
| format | Article |
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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.</description><identifier>ISSN: 1525-0016</identifier><identifier>EISSN: 1525-0024</identifier><identifier>DOI: 10.1038/mt.2014.153</identifier><identifier>PMID: 25101598</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Brain - metabolism ; Brain - pathology ; Disease Models, Animal ; Drug dosages ; Gene Silencing ; Genes ; Humans ; Huntingtin Protein ; Huntington Disease - genetics ; Huntington Disease - pathology ; Huntington Disease - therapy ; Injections ; Mice ; Mice, Inbred C57BL ; Molecular Targeted Therapy ; Mutant Proteins - metabolism ; Nerve Tissue Proteins - genetics ; Nerve Tissue Proteins - metabolism ; Oligonucleotides, Antisense - administration & dosage ; Oligonucleotides, Antisense - pharmacology ; Original ; Polymorphism, Single Nucleotide ; Proteins ; Rats ; Rats, Sprague-Dawley ; Thionucleotides - administration & dosage ; Thionucleotides - pharmacology</subject><ispartof>Molecular therapy, 2014-12, Vol.22 (12), p.2093-2106</ispartof><rights>2014 American Society of Gene & Cell Therapy</rights><rights>Copyright Nature Publishing Group Dec 2014</rights><rights>Copyright © 2014 American Society of Gene & Cell Therapy 2014 American Society of Gene & Cell Therapy</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c624t-617492b3dee33a53078c47a3fc09ae77ff2ce9e9de15dfc03242634cd91e085b3</citedby><cites>FETCH-LOGICAL-c624t-617492b3dee33a53078c47a3fc09ae77ff2ce9e9de15dfc03242634cd91e085b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4429695/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4429695/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25101598$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Southwell, Amber L</creatorcontrib><creatorcontrib>Skotte, Niels H</creatorcontrib><creatorcontrib>Kordasiewicz, Holly B</creatorcontrib><creatorcontrib>Østergaard, Michael E</creatorcontrib><creatorcontrib>Watt, Andrew T</creatorcontrib><creatorcontrib>Carroll, Jeffrey B</creatorcontrib><creatorcontrib>Doty, Crystal N</creatorcontrib><creatorcontrib>Villanueva, Erika B</creatorcontrib><creatorcontrib>Petoukhov, Eugenia</creatorcontrib><creatorcontrib>Vaid, Kuljeet</creatorcontrib><creatorcontrib>Xie, Yuanyun</creatorcontrib><creatorcontrib>Freier, Susan M</creatorcontrib><creatorcontrib>Swayze, Eric E</creatorcontrib><creatorcontrib>Seth, Punit P</creatorcontrib><creatorcontrib>Bennett, Clarence Frank</creatorcontrib><creatorcontrib>Hayden, Michael R</creatorcontrib><title>In Vivo Evaluation of Candidate Allele-specific Mutant Huntingtin Gene Silencing Antisense Oligonucleotides</title><title>Molecular therapy</title><addtitle>Mol Ther</addtitle><description>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.</description><subject>Animals</subject><subject>Brain - metabolism</subject><subject>Brain - pathology</subject><subject>Disease Models, Animal</subject><subject>Drug dosages</subject><subject>Gene Silencing</subject><subject>Genes</subject><subject>Humans</subject><subject>Huntingtin Protein</subject><subject>Huntington Disease - genetics</subject><subject>Huntington Disease - pathology</subject><subject>Huntington Disease - therapy</subject><subject>Injections</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Molecular Targeted Therapy</subject><subject>Mutant Proteins - metabolism</subject><subject>Nerve Tissue Proteins - genetics</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>Oligonucleotides, Antisense - administration & dosage</subject><subject>Oligonucleotides, Antisense - pharmacology</subject><subject>Original</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Proteins</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Thionucleotides - administration & dosage</subject><subject>Thionucleotides - 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Disease - pathology</topic><topic>Huntington Disease - therapy</topic><topic>Injections</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Molecular Targeted Therapy</topic><topic>Mutant Proteins - metabolism</topic><topic>Nerve Tissue Proteins - genetics</topic><topic>Nerve Tissue Proteins - metabolism</topic><topic>Oligonucleotides, Antisense - administration & dosage</topic><topic>Oligonucleotides, Antisense - pharmacology</topic><topic>Original</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Proteins</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Thionucleotides - administration & dosage</topic><topic>Thionucleotides - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Southwell, Amber L</creatorcontrib><creatorcontrib>Skotte, Niels H</creatorcontrib><creatorcontrib>Kordasiewicz, Holly B</creatorcontrib><creatorcontrib>Østergaard, Michael E</creatorcontrib><creatorcontrib>Watt, 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titles)</collection><jtitle>Molecular therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Southwell, Amber L</au><au>Skotte, Niels H</au><au>Kordasiewicz, Holly B</au><au>Østergaard, Michael E</au><au>Watt, Andrew T</au><au>Carroll, Jeffrey B</au><au>Doty, Crystal N</au><au>Villanueva, Erika B</au><au>Petoukhov, Eugenia</au><au>Vaid, Kuljeet</au><au>Xie, Yuanyun</au><au>Freier, Susan M</au><au>Swayze, Eric E</au><au>Seth, Punit P</au><au>Bennett, Clarence Frank</au><au>Hayden, Michael R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>In Vivo Evaluation of Candidate Allele-specific Mutant Huntingtin Gene Silencing Antisense Oligonucleotides</atitle><jtitle>Molecular therapy</jtitle><addtitle>Mol Ther</addtitle><date>2014-12-01</date><risdate>2014</risdate><volume>22</volume><issue>12</issue><spage>2093</spage><epage>2106</epage><pages>2093-2106</pages><issn>1525-0016</issn><eissn>1525-0024</eissn><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.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>25101598</pmid><doi>10.1038/mt.2014.153</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Brain - metabolism Brain - pathology Disease Models, Animal Drug dosages Gene Silencing Genes Humans Huntingtin Protein Huntington Disease - genetics Huntington Disease - pathology Huntington Disease - therapy Injections Mice Mice, Inbred C57BL Molecular Targeted Therapy Mutant Proteins - metabolism Nerve Tissue Proteins - genetics Nerve Tissue Proteins - metabolism Oligonucleotides, Antisense - administration & dosage Oligonucleotides, Antisense - pharmacology Original Polymorphism, Single Nucleotide Proteins Rats Rats, Sprague-Dawley Thionucleotides - administration & dosage Thionucleotides - pharmacology |
| title | In Vivo Evaluation of Candidate Allele-specific Mutant Huntingtin Gene Silencing Antisense Oligonucleotides |
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