Antisense Oligonucleotide Silencing Reverses Abnormal Neurochemistry in Spinocerebellar Ataxia 3 Mice
Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia, and biomarkers are needed to noninvasively monitor disease progression and treatment response. Anti-ATXN3 antisense oligonucleotide (ASO) treatment has been shown to mitigate neuropathology and rescue motor phenotyp...
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| Veröffentlicht in: | Annals of neurology 2023-10, Vol.94 (4), p.658-671 |
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| creator | McLoughlin, Hayley S Gundry, Katherine Rainwater, Orion Schuster, Kristen H Wellik, Isabel G Zalon, Annie J Benneyworth, Michael A Eberly, Lynn E Öz, Gülin |
| description | Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia, and biomarkers are needed to noninvasively monitor disease progression and treatment response. Anti-ATXN3 antisense oligonucleotide (ASO) treatment has been shown to mitigate neuropathology and rescue motor phenotypes in SCA3 mice. Here, we investigated whether repeated ASO administration reverses brainstem and cerebellar neurochemical abnormalities by magnetic resonance spectroscopy (MRS).
Symptomatic SCA3 mice received intracerebroventricular treatment of ASO or vehicle and were compared to wild-type vehicle-treated littermates. To quantify neurochemical changes in treated mice, longitudinal 9.4T MRS of cerebellum and brainstem was performed. Acquired magnetic resonance (MR) group means were analyzed by 2-way analysis of variance mixed-effects sex-adjusted analysis with post hoc Sidak correlation for multiple comparisons. Pearson correlations were used to relate SCA3 pathology and behavior.
MR spectra yielded 15 to 16 neurochemical concentrations in the cerebellum and brainstem. ASO treatment in SCA3 mice resulted in significant total choline rescue and partial reversals of taurine, glutamine, and total N-acetylaspartate across both regions. Some ASO-rescued neurochemicals correlated with reduction in diseased protein and nuclear ATXN3 accumulation. ASO-corrected motor activity correlated with total choline and total N-acetylaspartate levels early in disease.
SCA3 mouse cerebellar and brainstem neurochemical trends parallel those in patients with SCA3. Decreased total choline may reflect oligodendrocyte abnormalities, decreased total N-acetylaspartate highlights neuronal health disturbances, and high glutamine may indicate gliosis. ASO treatment fully or partially reversed select neurochemical abnormalities in SCA3 mice, indicating the potential for these measures to serve as noninvasive treatment biomarkers in future SCA3 gene silencing trials. ANN NEUROL 2023;94:658-671. |
| doi_str_mv | 10.1002/ana.26713 |
| format | Article |
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Symptomatic SCA3 mice received intracerebroventricular treatment of ASO or vehicle and were compared to wild-type vehicle-treated littermates. To quantify neurochemical changes in treated mice, longitudinal 9.4T MRS of cerebellum and brainstem was performed. Acquired magnetic resonance (MR) group means were analyzed by 2-way analysis of variance mixed-effects sex-adjusted analysis with post hoc Sidak correlation for multiple comparisons. Pearson correlations were used to relate SCA3 pathology and behavior.
MR spectra yielded 15 to 16 neurochemical concentrations in the cerebellum and brainstem. ASO treatment in SCA3 mice resulted in significant total choline rescue and partial reversals of taurine, glutamine, and total N-acetylaspartate across both regions. Some ASO-rescued neurochemicals correlated with reduction in diseased protein and nuclear ATXN3 accumulation. ASO-corrected motor activity correlated with total choline and total N-acetylaspartate levels early in disease.
SCA3 mouse cerebellar and brainstem neurochemical trends parallel those in patients with SCA3. Decreased total choline may reflect oligodendrocyte abnormalities, decreased total N-acetylaspartate highlights neuronal health disturbances, and high glutamine may indicate gliosis. ASO treatment fully or partially reversed select neurochemical abnormalities in SCA3 mice, indicating the potential for these measures to serve as noninvasive treatment biomarkers in future SCA3 gene silencing trials. ANN NEUROL 2023;94:658-671.</description><identifier>ISSN: 0364-5134</identifier><identifier>ISSN: 1531-8249</identifier><identifier>EISSN: 1531-8249</identifier><identifier>DOI: 10.1002/ana.26713</identifier><identifier>PMID: 37243335</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>Abnormalities ; Animals ; Antisense oligonucleotides ; Ataxia ; Biomarkers ; Brain stem ; Cerebellum ; Choline ; Choline - metabolism ; Clinical trials ; Correlation ; Gene silencing ; Gliosis ; Glutamine ; Humans ; Machado-Joseph disease ; Machado-Joseph Disease - genetics ; Machado-Joseph Disease - pathology ; Magnetic resonance spectroscopy ; Mice ; Motor activity ; Neurochemistry ; Oligonucleotides, Antisense - therapeutic use ; Phenotypes ; Spectrum analysis ; Taurine ; Variance analysis</subject><ispartof>Annals of neurology, 2023-10, Vol.94 (4), p.658-671</ispartof><rights>2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.</rights><rights>2023. This article is published under http://creativecommons.org/licenses/by-nc/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c348t-7833524b4f52cbe5be31a413f34d97367fa50fbc53e5c05279beba05635eba333</citedby><cites>FETCH-LOGICAL-c348t-7833524b4f52cbe5be31a413f34d97367fa50fbc53e5c05279beba05635eba333</cites><orcidid>0000-0002-5769-183X ; 0000-0003-4279-2758</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37243335$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>McLoughlin, Hayley S</creatorcontrib><creatorcontrib>Gundry, Katherine</creatorcontrib><creatorcontrib>Rainwater, Orion</creatorcontrib><creatorcontrib>Schuster, Kristen H</creatorcontrib><creatorcontrib>Wellik, Isabel G</creatorcontrib><creatorcontrib>Zalon, Annie J</creatorcontrib><creatorcontrib>Benneyworth, Michael A</creatorcontrib><creatorcontrib>Eberly, Lynn E</creatorcontrib><creatorcontrib>Öz, Gülin</creatorcontrib><title>Antisense Oligonucleotide Silencing Reverses Abnormal Neurochemistry in Spinocerebellar Ataxia 3 Mice</title><title>Annals of neurology</title><addtitle>Ann Neurol</addtitle><description>Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia, and biomarkers are needed to noninvasively monitor disease progression and treatment response. Anti-ATXN3 antisense oligonucleotide (ASO) treatment has been shown to mitigate neuropathology and rescue motor phenotypes in SCA3 mice. Here, we investigated whether repeated ASO administration reverses brainstem and cerebellar neurochemical abnormalities by magnetic resonance spectroscopy (MRS).
Symptomatic SCA3 mice received intracerebroventricular treatment of ASO or vehicle and were compared to wild-type vehicle-treated littermates. To quantify neurochemical changes in treated mice, longitudinal 9.4T MRS of cerebellum and brainstem was performed. Acquired magnetic resonance (MR) group means were analyzed by 2-way analysis of variance mixed-effects sex-adjusted analysis with post hoc Sidak correlation for multiple comparisons. Pearson correlations were used to relate SCA3 pathology and behavior.
MR spectra yielded 15 to 16 neurochemical concentrations in the cerebellum and brainstem. ASO treatment in SCA3 mice resulted in significant total choline rescue and partial reversals of taurine, glutamine, and total N-acetylaspartate across both regions. Some ASO-rescued neurochemicals correlated with reduction in diseased protein and nuclear ATXN3 accumulation. ASO-corrected motor activity correlated with total choline and total N-acetylaspartate levels early in disease.
SCA3 mouse cerebellar and brainstem neurochemical trends parallel those in patients with SCA3. Decreased total choline may reflect oligodendrocyte abnormalities, decreased total N-acetylaspartate highlights neuronal health disturbances, and high glutamine may indicate gliosis. ASO treatment fully or partially reversed select neurochemical abnormalities in SCA3 mice, indicating the potential for these measures to serve as noninvasive treatment biomarkers in future SCA3 gene silencing trials. ANN NEUROL 2023;94:658-671.</description><subject>Abnormalities</subject><subject>Animals</subject><subject>Antisense oligonucleotides</subject><subject>Ataxia</subject><subject>Biomarkers</subject><subject>Brain stem</subject><subject>Cerebellum</subject><subject>Choline</subject><subject>Choline - metabolism</subject><subject>Clinical trials</subject><subject>Correlation</subject><subject>Gene silencing</subject><subject>Gliosis</subject><subject>Glutamine</subject><subject>Humans</subject><subject>Machado-Joseph disease</subject><subject>Machado-Joseph Disease - genetics</subject><subject>Machado-Joseph Disease - pathology</subject><subject>Magnetic resonance spectroscopy</subject><subject>Mice</subject><subject>Motor activity</subject><subject>Neurochemistry</subject><subject>Oligonucleotides, Antisense - therapeutic use</subject><subject>Phenotypes</subject><subject>Spectrum analysis</subject><subject>Taurine</subject><subject>Variance analysis</subject><issn>0364-5134</issn><issn>1531-8249</issn><issn>1531-8249</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkMtOwzAQRS0EglJY8APIEhtYpNgeO0mXFeIl8ZB4rCPbnYBRahc7QfD3GCgsWN3Nmas7h5A9ziacMXGsvZ6IsuKwRkZcAS9qIafrZMSglIXiILfIdkovjLFpydkm2YJKSABQI4Iz37uEPiG97dxT8IPtMPRujvTedeit80_0Dt8wJkx0ZnyIC93RGxxisM-4cKmPH9R5er90PliMaLDrdKSzXr87TYFeO4s7ZKPVXcLdVY7J49npw8lFcXV7fnkyuyosyLovqjpvEtLIVglrUBkEriWHFuR8WkFZtVqx1lgFqCxTopoaNJqpElTO_NCYHP70LmN4HTD1TR5ovwZ5DENqRC2yL1nnizE5-Ie-hCH6vC5TFQMFdVln6uiHsjGkFLFtltEtdPxoOGu-3DfZffPtPrP7q8bBLHD-R_7Khk8R137-</recordid><startdate>20231001</startdate><enddate>20231001</enddate><creator>McLoughlin, Hayley S</creator><creator>Gundry, Katherine</creator><creator>Rainwater, Orion</creator><creator>Schuster, Kristen H</creator><creator>Wellik, Isabel G</creator><creator>Zalon, Annie J</creator><creator>Benneyworth, Michael A</creator><creator>Eberly, Lynn E</creator><creator>Öz, Gülin</creator><general>Wiley Subscription Services, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7U7</scope><scope>C1K</scope><scope>K9.</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-5769-183X</orcidid><orcidid>https://orcid.org/0000-0003-4279-2758</orcidid></search><sort><creationdate>20231001</creationdate><title>Antisense Oligonucleotide Silencing Reverses Abnormal Neurochemistry in Spinocerebellar Ataxia 3 Mice</title><author>McLoughlin, Hayley S ; Gundry, Katherine ; Rainwater, Orion ; Schuster, Kristen H ; Wellik, Isabel G ; Zalon, Annie J ; Benneyworth, Michael A ; Eberly, Lynn E ; Öz, Gülin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c348t-7833524b4f52cbe5be31a413f34d97367fa50fbc53e5c05279beba05635eba333</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Abnormalities</topic><topic>Animals</topic><topic>Antisense oligonucleotides</topic><topic>Ataxia</topic><topic>Biomarkers</topic><topic>Brain stem</topic><topic>Cerebellum</topic><topic>Choline</topic><topic>Choline - metabolism</topic><topic>Clinical trials</topic><topic>Correlation</topic><topic>Gene silencing</topic><topic>Gliosis</topic><topic>Glutamine</topic><topic>Humans</topic><topic>Machado-Joseph disease</topic><topic>Machado-Joseph Disease - genetics</topic><topic>Machado-Joseph Disease - pathology</topic><topic>Magnetic resonance spectroscopy</topic><topic>Mice</topic><topic>Motor activity</topic><topic>Neurochemistry</topic><topic>Oligonucleotides, Antisense - therapeutic use</topic><topic>Phenotypes</topic><topic>Spectrum analysis</topic><topic>Taurine</topic><topic>Variance analysis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>McLoughlin, Hayley S</creatorcontrib><creatorcontrib>Gundry, Katherine</creatorcontrib><creatorcontrib>Rainwater, Orion</creatorcontrib><creatorcontrib>Schuster, Kristen H</creatorcontrib><creatorcontrib>Wellik, Isabel G</creatorcontrib><creatorcontrib>Zalon, Annie J</creatorcontrib><creatorcontrib>Benneyworth, Michael A</creatorcontrib><creatorcontrib>Eberly, Lynn E</creatorcontrib><creatorcontrib>Öz, Gülin</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Annals of neurology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>McLoughlin, Hayley S</au><au>Gundry, Katherine</au><au>Rainwater, Orion</au><au>Schuster, Kristen H</au><au>Wellik, Isabel G</au><au>Zalon, Annie J</au><au>Benneyworth, Michael A</au><au>Eberly, Lynn E</au><au>Öz, Gülin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Antisense Oligonucleotide Silencing Reverses Abnormal Neurochemistry in Spinocerebellar Ataxia 3 Mice</atitle><jtitle>Annals of neurology</jtitle><addtitle>Ann Neurol</addtitle><date>2023-10-01</date><risdate>2023</risdate><volume>94</volume><issue>4</issue><spage>658</spage><epage>671</epage><pages>658-671</pages><issn>0364-5134</issn><issn>1531-8249</issn><eissn>1531-8249</eissn><abstract>Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia, and biomarkers are needed to noninvasively monitor disease progression and treatment response. Anti-ATXN3 antisense oligonucleotide (ASO) treatment has been shown to mitigate neuropathology and rescue motor phenotypes in SCA3 mice. Here, we investigated whether repeated ASO administration reverses brainstem and cerebellar neurochemical abnormalities by magnetic resonance spectroscopy (MRS).
Symptomatic SCA3 mice received intracerebroventricular treatment of ASO or vehicle and were compared to wild-type vehicle-treated littermates. To quantify neurochemical changes in treated mice, longitudinal 9.4T MRS of cerebellum and brainstem was performed. Acquired magnetic resonance (MR) group means were analyzed by 2-way analysis of variance mixed-effects sex-adjusted analysis with post hoc Sidak correlation for multiple comparisons. Pearson correlations were used to relate SCA3 pathology and behavior.
MR spectra yielded 15 to 16 neurochemical concentrations in the cerebellum and brainstem. ASO treatment in SCA3 mice resulted in significant total choline rescue and partial reversals of taurine, glutamine, and total N-acetylaspartate across both regions. Some ASO-rescued neurochemicals correlated with reduction in diseased protein and nuclear ATXN3 accumulation. ASO-corrected motor activity correlated with total choline and total N-acetylaspartate levels early in disease.
SCA3 mouse cerebellar and brainstem neurochemical trends parallel those in patients with SCA3. Decreased total choline may reflect oligodendrocyte abnormalities, decreased total N-acetylaspartate highlights neuronal health disturbances, and high glutamine may indicate gliosis. ASO treatment fully or partially reversed select neurochemical abnormalities in SCA3 mice, indicating the potential for these measures to serve as noninvasive treatment biomarkers in future SCA3 gene silencing trials. ANN NEUROL 2023;94:658-671.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>37243335</pmid><doi>10.1002/ana.26713</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0002-5769-183X</orcidid><orcidid>https://orcid.org/0000-0003-4279-2758</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Abnormalities Animals Antisense oligonucleotides Ataxia Biomarkers Brain stem Cerebellum Choline Choline - metabolism Clinical trials Correlation Gene silencing Gliosis Glutamine Humans Machado-Joseph disease Machado-Joseph Disease - genetics Machado-Joseph Disease - pathology Magnetic resonance spectroscopy Mice Motor activity Neurochemistry Oligonucleotides, Antisense - therapeutic use Phenotypes Spectrum analysis Taurine Variance analysis |
| title | Antisense Oligonucleotide Silencing Reverses Abnormal Neurochemistry in Spinocerebellar Ataxia 3 Mice |
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