Long-Term Disease Prevention with a Gene Therapy Targeting Oligodendrocytes in a Mouse Model of Adrenomyeloneuropathy
Adrenomyeloneuropathy (AMN) is a late-onset axonopathy of spinal cord tracts caused by mutations of the ABCD1 gene that encodes adrenoleukodystrophy protein (ALDP), a peroxisomal transporter of very long-chain fatty acids (VLCFA). Disturbed metabolic interaction between oligodendrocytes (OL) and axo...
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Veröffentlicht in: | Human gene therapy 2022-09, Vol.33 (17-18), p.936-949 |
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creator | Özgür-Günes, Yasemin Chedik, Malha Le Stunff, Catherine Fovet, Claire-Maëlle Bougnères, Pierre |
description | Adrenomyeloneuropathy (AMN) is a late-onset axonopathy of spinal cord tracts caused by mutations of the ABCD1 gene that encodes adrenoleukodystrophy protein (ALDP), a peroxisomal transporter of very long-chain fatty acids (VLCFA). Disturbed metabolic interaction between oligodendrocytes (OL) and axons is suspected to play a major role in AMN axonopathy. To develop a vector targeting OL, the human ABCD1 gene driven by a short 0.3 kb part of the human myelin-associated glycoprotein (MAG) promoter was packaged into an adeno-associated viral serotype 9 (rAAV9). An intravenous injection of this vector on postnatal day 10 in Abcd1
mice, a model of AMN, allowed a near normal motor performance to persist for 24 months, while age-matched untreated mice developed major defects of balance and motricity. Three weeks postvector, 50-54% of spinal cord white matter OL was expressing human ALDP (hALDP) at the cervical level, and only 6-7% after 24 months. In addition, 29-32% of cervical spinal cord astrocytes at 3 weeks and 16-19% at 24 months also expressed ALDP. C26:0-lysoPC, a sensitive VLCFA marker of AMN, was lower by 41% and 50%, respectively, in the spinal cord and brain of vector-treated compared with untreated mice. In a nonhuman primate, the intrathecal injection of the rAAV9-MAG vector induced abundant ALDP expression at 3 weeks in spinal cord OL (43%, 29%, and 26% at cervical, thoracic, and lumbar levels) and cerebellum OL (35%). In addition, 33-41% of spinal cord astrocytes expressed hALDP, and 27% of cerebellar astrocytes. To our knowledge, OL targeting had not been obtained before in primates with other vectors or promoters. The current results thus provide a robust proof-of-concept not only for the gene therapy of AMN but also for other central nervous system diseases, where the targeting of OL with the rAAV9-MAG vector may be of interest. |
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mice, a model of AMN, allowed a near normal motor performance to persist for 24 months, while age-matched untreated mice developed major defects of balance and motricity. Three weeks postvector, 50-54% of spinal cord white matter OL was expressing human ALDP (hALDP) at the cervical level, and only 6-7% after 24 months. In addition, 29-32% of cervical spinal cord astrocytes at 3 weeks and 16-19% at 24 months also expressed ALDP. C26:0-lysoPC, a sensitive VLCFA marker of AMN, was lower by 41% and 50%, respectively, in the spinal cord and brain of vector-treated compared with untreated mice. In a nonhuman primate, the intrathecal injection of the rAAV9-MAG vector induced abundant ALDP expression at 3 weeks in spinal cord OL (43%, 29%, and 26% at cervical, thoracic, and lumbar levels) and cerebellum OL (35%). In addition, 33-41% of spinal cord astrocytes expressed hALDP, and 27% of cerebellar astrocytes. To our knowledge, OL targeting had not been obtained before in primates with other vectors or promoters. The current results thus provide a robust proof-of-concept not only for the gene therapy of AMN but also for other central nervous system diseases, where the targeting of OL with the rAAV9-MAG vector may be of interest.</description><identifier>ISSN: 1043-0342</identifier><identifier>EISSN: 1557-7422</identifier><identifier>DOI: 10.1089/hum.2021.293</identifier><identifier>PMID: 35166123</identifier><language>eng</language><publisher>United States: Mary Ann Liebert, Inc</publisher><subject>Adrenoleukodystrophy ; Adrenoleukodystrophy - genetics ; Adrenoleukodystrophy - therapy ; Animals ; Astrocytes ; ATP Binding Cassette Transporter, Subfamily D, Member 1 - genetics ; Axons ; Central nervous system ; Central nervous system diseases ; Cerebellum ; Disease control ; Disease Models, Animal ; Fatty acids ; Fatty Acids - metabolism ; Gene therapy ; Genetic Therapy ; Glycoproteins ; Humans ; Injection ; Intravenous administration ; Mice ; Motor task performance ; Mutation ; Myelin ; Myelin-associated glycoprotein ; Myelin-Associated Glycoprotein - genetics ; Myelin-Associated Glycoprotein - metabolism ; Oligodendrocytes ; Oligodendroglia - metabolism ; Primates ; Protein transport ; Spinal cord ; Substantia alba ; Thorax</subject><ispartof>Human gene therapy, 2022-09, Vol.33 (17-18), p.936-949</ispartof><rights>Copyright Mary Ann Liebert, Inc. Sep 2022</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c249t-784600ec836332a513f3ac059ee4d71dccde9971f72df593c3d5f159ae911fa13</citedby><cites>FETCH-LOGICAL-c249t-784600ec836332a513f3ac059ee4d71dccde9971f72df593c3d5f159ae911fa13</cites><orcidid>0000-0003-0017-4572</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/35166123$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Özgür-Günes, Yasemin</creatorcontrib><creatorcontrib>Chedik, Malha</creatorcontrib><creatorcontrib>Le Stunff, Catherine</creatorcontrib><creatorcontrib>Fovet, Claire-Maëlle</creatorcontrib><creatorcontrib>Bougnères, Pierre</creatorcontrib><title>Long-Term Disease Prevention with a Gene Therapy Targeting Oligodendrocytes in a Mouse Model of Adrenomyeloneuropathy</title><title>Human gene therapy</title><addtitle>Hum Gene Ther</addtitle><description>Adrenomyeloneuropathy (AMN) is a late-onset axonopathy of spinal cord tracts caused by mutations of the ABCD1 gene that encodes adrenoleukodystrophy protein (ALDP), a peroxisomal transporter of very long-chain fatty acids (VLCFA). Disturbed metabolic interaction between oligodendrocytes (OL) and axons is suspected to play a major role in AMN axonopathy. To develop a vector targeting OL, the human ABCD1 gene driven by a short 0.3 kb part of the human myelin-associated glycoprotein (MAG) promoter was packaged into an adeno-associated viral serotype 9 (rAAV9). An intravenous injection of this vector on postnatal day 10 in Abcd1
mice, a model of AMN, allowed a near normal motor performance to persist for 24 months, while age-matched untreated mice developed major defects of balance and motricity. Three weeks postvector, 50-54% of spinal cord white matter OL was expressing human ALDP (hALDP) at the cervical level, and only 6-7% after 24 months. In addition, 29-32% of cervical spinal cord astrocytes at 3 weeks and 16-19% at 24 months also expressed ALDP. C26:0-lysoPC, a sensitive VLCFA marker of AMN, was lower by 41% and 50%, respectively, in the spinal cord and brain of vector-treated compared with untreated mice. In a nonhuman primate, the intrathecal injection of the rAAV9-MAG vector induced abundant ALDP expression at 3 weeks in spinal cord OL (43%, 29%, and 26% at cervical, thoracic, and lumbar levels) and cerebellum OL (35%). In addition, 33-41% of spinal cord astrocytes expressed hALDP, and 27% of cerebellar astrocytes. To our knowledge, OL targeting had not been obtained before in primates with other vectors or promoters. The current results thus provide a robust proof-of-concept not only for the gene therapy of AMN but also for other central nervous system diseases, where the targeting of OL with the rAAV9-MAG vector may be of interest.</description><subject>Adrenoleukodystrophy</subject><subject>Adrenoleukodystrophy - genetics</subject><subject>Adrenoleukodystrophy - therapy</subject><subject>Animals</subject><subject>Astrocytes</subject><subject>ATP Binding Cassette Transporter, Subfamily D, Member 1 - genetics</subject><subject>Axons</subject><subject>Central nervous system</subject><subject>Central nervous system diseases</subject><subject>Cerebellum</subject><subject>Disease control</subject><subject>Disease Models, Animal</subject><subject>Fatty acids</subject><subject>Fatty Acids - metabolism</subject><subject>Gene therapy</subject><subject>Genetic Therapy</subject><subject>Glycoproteins</subject><subject>Humans</subject><subject>Injection</subject><subject>Intravenous administration</subject><subject>Mice</subject><subject>Motor task performance</subject><subject>Mutation</subject><subject>Myelin</subject><subject>Myelin-associated glycoprotein</subject><subject>Myelin-Associated Glycoprotein - genetics</subject><subject>Myelin-Associated Glycoprotein - metabolism</subject><subject>Oligodendrocytes</subject><subject>Oligodendroglia - metabolism</subject><subject>Primates</subject><subject>Protein transport</subject><subject>Spinal cord</subject><subject>Substantia alba</subject><subject>Thorax</subject><issn>1043-0342</issn><issn>1557-7422</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkU1P3DAQhi3Uiu8b58pSLz00W9sTx-sjgpYiLYLDcraMPdkNSuytnVDl32MK5cBpRppHj17NS8gZZwvOlvrHdhoWggm-EBr2yCGXUlWqFuJT2VkNFYNaHJCjnB8Z4yAbtU8OQPKm4QIOybSKYVOtMQ30sstoM9K7hE8Yxi4G-rcbt9TSKwxI11tMdjfTtU0bHLuwobd9t4keg0_RzSNm2oUC38SpSG7Koaexpec-YYjDjH0MOKW4s-N2PiGfW9tnPH2bx-T-18_1xe9qdXt1fXG-qpyo9VipZd0whm4JDYCwkkML1jGpEWuvuHfOo9aKt0r4Vmpw4GXLpbaoOW8th2Py7dW7S_HPhHk0Q5cd9r0NWGIa0QhddBpYQb9-QB_jlEJJZ4TiUi0VaCjU91fKpZhzwtbsUjfYNBvOzEsdptRhXuow4h_-5U06PQzo3-H__4dnpKyGWA</recordid><startdate>202209</startdate><enddate>202209</enddate><creator>Özgür-Günes, Yasemin</creator><creator>Chedik, Malha</creator><creator>Le Stunff, Catherine</creator><creator>Fovet, Claire-Maëlle</creator><creator>Bougnères, Pierre</creator><general>Mary Ann Liebert, 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>7QO</scope><scope>7QP</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-0017-4572</orcidid></search><sort><creationdate>202209</creationdate><title>Long-Term Disease Prevention with a Gene Therapy Targeting Oligodendrocytes in a Mouse Model of Adrenomyeloneuropathy</title><author>Özgür-Günes, Yasemin ; Chedik, Malha ; Le Stunff, Catherine ; Fovet, Claire-Maëlle ; Bougnères, Pierre</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c249t-784600ec836332a513f3ac059ee4d71dccde9971f72df593c3d5f159ae911fa13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Adrenoleukodystrophy</topic><topic>Adrenoleukodystrophy - genetics</topic><topic>Adrenoleukodystrophy - therapy</topic><topic>Animals</topic><topic>Astrocytes</topic><topic>ATP Binding Cassette Transporter, Subfamily D, Member 1 - genetics</topic><topic>Axons</topic><topic>Central nervous system</topic><topic>Central nervous system diseases</topic><topic>Cerebellum</topic><topic>Disease control</topic><topic>Disease Models, Animal</topic><topic>Fatty acids</topic><topic>Fatty Acids - metabolism</topic><topic>Gene therapy</topic><topic>Genetic Therapy</topic><topic>Glycoproteins</topic><topic>Humans</topic><topic>Injection</topic><topic>Intravenous administration</topic><topic>Mice</topic><topic>Motor task performance</topic><topic>Mutation</topic><topic>Myelin</topic><topic>Myelin-associated glycoprotein</topic><topic>Myelin-Associated Glycoprotein - genetics</topic><topic>Myelin-Associated Glycoprotein - metabolism</topic><topic>Oligodendrocytes</topic><topic>Oligodendroglia - metabolism</topic><topic>Primates</topic><topic>Protein transport</topic><topic>Spinal cord</topic><topic>Substantia alba</topic><topic>Thorax</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Özgür-Günes, Yasemin</creatorcontrib><creatorcontrib>Chedik, Malha</creatorcontrib><creatorcontrib>Le Stunff, Catherine</creatorcontrib><creatorcontrib>Fovet, Claire-Maëlle</creatorcontrib><creatorcontrib>Bougnères, Pierre</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Human gene therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Özgür-Günes, Yasemin</au><au>Chedik, Malha</au><au>Le Stunff, Catherine</au><au>Fovet, Claire-Maëlle</au><au>Bougnères, Pierre</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Long-Term Disease Prevention with a Gene Therapy Targeting Oligodendrocytes in a Mouse Model of Adrenomyeloneuropathy</atitle><jtitle>Human gene therapy</jtitle><addtitle>Hum Gene Ther</addtitle><date>2022-09</date><risdate>2022</risdate><volume>33</volume><issue>17-18</issue><spage>936</spage><epage>949</epage><pages>936-949</pages><issn>1043-0342</issn><eissn>1557-7422</eissn><abstract>Adrenomyeloneuropathy (AMN) is a late-onset axonopathy of spinal cord tracts caused by mutations of the ABCD1 gene that encodes adrenoleukodystrophy protein (ALDP), a peroxisomal transporter of very long-chain fatty acids (VLCFA). Disturbed metabolic interaction between oligodendrocytes (OL) and axons is suspected to play a major role in AMN axonopathy. To develop a vector targeting OL, the human ABCD1 gene driven by a short 0.3 kb part of the human myelin-associated glycoprotein (MAG) promoter was packaged into an adeno-associated viral serotype 9 (rAAV9). An intravenous injection of this vector on postnatal day 10 in Abcd1
mice, a model of AMN, allowed a near normal motor performance to persist for 24 months, while age-matched untreated mice developed major defects of balance and motricity. Three weeks postvector, 50-54% of spinal cord white matter OL was expressing human ALDP (hALDP) at the cervical level, and only 6-7% after 24 months. In addition, 29-32% of cervical spinal cord astrocytes at 3 weeks and 16-19% at 24 months also expressed ALDP. C26:0-lysoPC, a sensitive VLCFA marker of AMN, was lower by 41% and 50%, respectively, in the spinal cord and brain of vector-treated compared with untreated mice. In a nonhuman primate, the intrathecal injection of the rAAV9-MAG vector induced abundant ALDP expression at 3 weeks in spinal cord OL (43%, 29%, and 26% at cervical, thoracic, and lumbar levels) and cerebellum OL (35%). In addition, 33-41% of spinal cord astrocytes expressed hALDP, and 27% of cerebellar astrocytes. To our knowledge, OL targeting had not been obtained before in primates with other vectors or promoters. The current results thus provide a robust proof-of-concept not only for the gene therapy of AMN but also for other central nervous system diseases, where the targeting of OL with the rAAV9-MAG vector may be of interest.</abstract><cop>United States</cop><pub>Mary Ann Liebert, Inc</pub><pmid>35166123</pmid><doi>10.1089/hum.2021.293</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0003-0017-4572</orcidid></addata></record> |
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subjects | Adrenoleukodystrophy Adrenoleukodystrophy - genetics Adrenoleukodystrophy - therapy Animals Astrocytes ATP Binding Cassette Transporter, Subfamily D, Member 1 - genetics Axons Central nervous system Central nervous system diseases Cerebellum Disease control Disease Models, Animal Fatty acids Fatty Acids - metabolism Gene therapy Genetic Therapy Glycoproteins Humans Injection Intravenous administration Mice Motor task performance Mutation Myelin Myelin-associated glycoprotein Myelin-Associated Glycoprotein - genetics Myelin-Associated Glycoprotein - metabolism Oligodendrocytes Oligodendroglia - metabolism Primates Protein transport Spinal cord Substantia alba Thorax |
title | Long-Term Disease Prevention with a Gene Therapy Targeting Oligodendrocytes in a Mouse Model of Adrenomyeloneuropathy |
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