A Single Intravenous rAAV Injection as Late as P20 Achieves Efficacious and Sustained CNS Gene Therapy in Canavan Mice
Canavan’s disease (CD) is a fatal pediatric leukodystrophy caused by mutations in aspartoacylase (AspA) gene. Currently, there is no effective treatment for CD; however, gene therapy is an attractive approach to ameliorate the disease. Here, we studied progressive neuropathology and gene therapy in...
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| Veröffentlicht in: | Molecular therapy 2013-12, Vol.21 (12), p.2136-2147 |
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| creator | Ahmed, Seemin Seher Li, Huapeng Cao, Chunyan Sikoglu, Elif M Denninger, Andrew R Su, Qin Eaton, Samuel Liso Navarro, Ana A Xie, Jun Szucs, Sylvia Zhang, Hongwei Moore, Constance Kirschner, Daniel A Seyfried, Thomas N Flotte, Terence R Matalon, Reuben Gao, Guangping |
| description | Canavan’s disease (CD) is a fatal pediatric leukodystrophy caused by mutations in aspartoacylase (AspA) gene. Currently, there is no effective treatment for CD; however, gene therapy is an attractive approach to ameliorate the disease. Here, we studied progressive neuropathology and gene therapy in short-lived (≤1 month) AspA−/− mice, a bona-fide animal model for the severest form of CD. Single intravenous (IV) injections of several primate-derived recombinant adeno-associated viruses (rAAVs) as late as postnatal day 20 (P20) completely rescued their early lethality and alleviated the major disease symptoms, extending survival in P0-injected rAAV9 and rAAVrh8 groups to as long as 2 years thus far. We successfully used microRNA (miRNA)-mediated post-transcriptional detargeting for the first time to restrict therapeutic rAAV expression in the central nervous system (CNS) and minimize potentially deleterious effects of transgene overexpression in peripheral tissues. rAAV treatment globally improved CNS myelination, although some abnormalities persisted in the content and distribution of myelin-specific and -enriched lipids. We demonstrate that systemically delivered and CNS-restricted rAAVs can serve as efficacious and sustained gene therapeutics in a model of a severe neurodegenerative disorder even when administered as late as P20. |
| doi_str_mv | 10.1038/mt.2013.138 |
| format | Article |
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Currently, there is no effective treatment for CD; however, gene therapy is an attractive approach to ameliorate the disease. Here, we studied progressive neuropathology and gene therapy in short-lived (≤1 month) AspA−/− mice, a bona-fide animal model for the severest form of CD. Single intravenous (IV) injections of several primate-derived recombinant adeno-associated viruses (rAAVs) as late as postnatal day 20 (P20) completely rescued their early lethality and alleviated the major disease symptoms, extending survival in P0-injected rAAV9 and rAAVrh8 groups to as long as 2 years thus far. We successfully used microRNA (miRNA)-mediated post-transcriptional detargeting for the first time to restrict therapeutic rAAV expression in the central nervous system (CNS) and minimize potentially deleterious effects of transgene overexpression in peripheral tissues. rAAV treatment globally improved CNS myelination, although some abnormalities persisted in the content and distribution of myelin-specific and -enriched lipids. We demonstrate that systemically delivered and CNS-restricted rAAVs can serve as efficacious and sustained gene therapeutics in a model of a severe neurodegenerative disorder even when administered as late as P20.</description><identifier>ISSN: 1525-0016</identifier><identifier>EISSN: 1525-0024</identifier><identifier>DOI: 10.1038/mt.2013.138</identifier><identifier>PMID: 23817205</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Amidohydrolases - deficiency ; Amidohydrolases - genetics ; Amidohydrolases - metabolism ; Animals ; Animals, Newborn ; Brain ; Canavan Disease - pathology ; Canavan Disease - therapy ; Central Nervous System - metabolism ; Central Nervous System - pathology ; Dependovirus - genetics ; Disease Models, Animal ; Enzymes ; Gene Knockout Techniques ; Gene therapy ; Genetic Therapy ; Genetic Vectors ; Humans ; Injections, Intravenous ; Medical schools ; Mice ; MicroRNAs ; MicroRNAs - genetics ; Mutation ; Nervous system ; Neuropathology ; Organ Specificity ; Original ; Pediatrics ; X-Ray Diffraction</subject><ispartof>Molecular therapy, 2013-12, Vol.21 (12), p.2136-2147</ispartof><rights>2013 The American Society of Gene & Cell Therapy</rights><rights>Copyright Nature Publishing Group Dec 2013</rights><rights>Copyright © 2013 The American Society of Gene & Cell Therapy 2013 The American Society of Gene & Cell Therapy</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c488t-5f96ff0c5d928d93b19881859c130aadeb848cc912b6cce3ea080ca5641e4a423</citedby><cites>FETCH-LOGICAL-c488t-5f96ff0c5d928d93b19881859c130aadeb848cc912b6cce3ea080ca5641e4a423</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/PMC3863789/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1791884655?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>230,315,729,782,786,887,27931,27932,53798,53800,64392,64394,64396,72476</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23817205$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ahmed, Seemin Seher</creatorcontrib><creatorcontrib>Li, Huapeng</creatorcontrib><creatorcontrib>Cao, Chunyan</creatorcontrib><creatorcontrib>Sikoglu, Elif M</creatorcontrib><creatorcontrib>Denninger, Andrew R</creatorcontrib><creatorcontrib>Su, Qin</creatorcontrib><creatorcontrib>Eaton, Samuel</creatorcontrib><creatorcontrib>Liso Navarro, Ana A</creatorcontrib><creatorcontrib>Xie, Jun</creatorcontrib><creatorcontrib>Szucs, Sylvia</creatorcontrib><creatorcontrib>Zhang, Hongwei</creatorcontrib><creatorcontrib>Moore, Constance</creatorcontrib><creatorcontrib>Kirschner, Daniel A</creatorcontrib><creatorcontrib>Seyfried, Thomas N</creatorcontrib><creatorcontrib>Flotte, Terence R</creatorcontrib><creatorcontrib>Matalon, Reuben</creatorcontrib><creatorcontrib>Gao, Guangping</creatorcontrib><title>A Single Intravenous rAAV Injection as Late as P20 Achieves Efficacious and Sustained CNS Gene Therapy in Canavan Mice</title><title>Molecular therapy</title><addtitle>Mol Ther</addtitle><description>Canavan’s disease (CD) is a fatal pediatric leukodystrophy caused by mutations in aspartoacylase (AspA) gene. Currently, there is no effective treatment for CD; however, gene therapy is an attractive approach to ameliorate the disease. Here, we studied progressive neuropathology and gene therapy in short-lived (≤1 month) AspA−/− mice, a bona-fide animal model for the severest form of CD. Single intravenous (IV) injections of several primate-derived recombinant adeno-associated viruses (rAAVs) as late as postnatal day 20 (P20) completely rescued their early lethality and alleviated the major disease symptoms, extending survival in P0-injected rAAV9 and rAAVrh8 groups to as long as 2 years thus far. We successfully used microRNA (miRNA)-mediated post-transcriptional detargeting for the first time to restrict therapeutic rAAV expression in the central nervous system (CNS) and minimize potentially deleterious effects of transgene overexpression in peripheral tissues. rAAV treatment globally improved CNS myelination, although some abnormalities persisted in the content and distribution of myelin-specific and -enriched lipids. 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Currently, there is no effective treatment for CD; however, gene therapy is an attractive approach to ameliorate the disease. Here, we studied progressive neuropathology and gene therapy in short-lived (≤1 month) AspA−/− mice, a bona-fide animal model for the severest form of CD. Single intravenous (IV) injections of several primate-derived recombinant adeno-associated viruses (rAAVs) as late as postnatal day 20 (P20) completely rescued their early lethality and alleviated the major disease symptoms, extending survival in P0-injected rAAV9 and rAAVrh8 groups to as long as 2 years thus far. We successfully used microRNA (miRNA)-mediated post-transcriptional detargeting for the first time to restrict therapeutic rAAV expression in the central nervous system (CNS) and minimize potentially deleterious effects of transgene overexpression in peripheral tissues. rAAV treatment globally improved CNS myelination, although some abnormalities persisted in the content and distribution of myelin-specific and -enriched lipids. We demonstrate that systemically delivered and CNS-restricted rAAVs can serve as efficacious and sustained gene therapeutics in a model of a severe neurodegenerative disorder even when administered as late as P20.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>23817205</pmid><doi>10.1038/mt.2013.138</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Amidohydrolases - deficiency Amidohydrolases - genetics Amidohydrolases - metabolism Animals Animals, Newborn Brain Canavan Disease - pathology Canavan Disease - therapy Central Nervous System - metabolism Central Nervous System - pathology Dependovirus - genetics Disease Models, Animal Enzymes Gene Knockout Techniques Gene therapy Genetic Therapy Genetic Vectors Humans Injections, Intravenous Medical schools Mice MicroRNAs MicroRNAs - genetics Mutation Nervous system Neuropathology Organ Specificity Original Pediatrics X-Ray Diffraction |
| title | A Single Intravenous rAAV Injection as Late as P20 Achieves Efficacious and Sustained CNS Gene Therapy in Canavan Mice |
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