A novel adeno-associated viral variant for efficient and selective intravitreal transduction of rat Müller cells.
BACKGROUND:The pathologies of numerous retinal degenerative diseases can be attributed to a multitude of genetic factors, and individualized treatment options for afflicted patients are limited and cost-inefficient. In light of the shared neurodegenerative phenotype among these disorders, a safe and...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2009-10-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2758586?pdf=render |
| _version_ | 1818933616056467456 |
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| author | Ryan R Klimczak James T Koerber Deniz Dalkara John G Flannery David V Schaffer |
| author_facet | Ryan R Klimczak James T Koerber Deniz Dalkara John G Flannery David V Schaffer |
| author_sort | Ryan R Klimczak |
| collection | DOAJ |
| description | BACKGROUND:The pathologies of numerous retinal degenerative diseases can be attributed to a multitude of genetic factors, and individualized treatment options for afflicted patients are limited and cost-inefficient. In light of the shared neurodegenerative phenotype among these disorders, a safe and broad-based neuroprotective approach would be desirable to overcome these obstacles. As a result, gene delivery of secretable-neuroprotective factors to Müller cells, a type of retinal glia that contacts all classes of retinal neurons, represents an ideal approach to mediate protection of the entire retina through a simple and innocuous intraocular, or intravitreal, injection of an efficient vehicle such as an adeno-associated viral vector (AAV). Although several naturally occurring AAV variants have been isolated with a variety of tropisms, or cellular specificities, these vectors inefficiently infect Müller cells via intravitreal injection. METHODOLOGY/PRINCIPAL FINDINGS:We have previously applied directed evolution to create several novel AAV variants capable of efficient infection of both rat and human astrocytes through iterative selection of a panel of highly diverse AAV libraries. Here, in vivo and in vitro characterization of these isolated variants identifies a previously unreported AAV variant ShH10, closely related to AAV serotype 6 (AAV6), capable of efficient, selective Müller cell infection through intravitreal injection. Importantly, this new variant shows significantly improved transduction relative to AAV2 (>60%) and AAV6. CONCLUSIONS/SIGNIFICANCE:Our findings demonstrate that AAV is a highly versatile vector capable of powerful shifts in tropism from minor sequence changes. This isolated variant represents a new therapeutic vector to treat retinal degenerative diseases through secretion of neuroprotective factors from Müller cells as well as provides new opportunities to study their biological functions in the retina. |
| first_indexed | 2024-12-20T04:51:12Z |
| format | Article |
| id | doaj.art-b967132127d04600aceba49f6aed8693 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-20T04:51:12Z |
| publishDate | 2009-10-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-b967132127d04600aceba49f6aed86932022-12-21T19:52:51ZengPublic Library of Science (PLoS)PLoS ONE1932-62032009-10-01410e746710.1371/journal.pone.0007467A novel adeno-associated viral variant for efficient and selective intravitreal transduction of rat Müller cells.Ryan R KlimczakJames T KoerberDeniz DalkaraJohn G FlanneryDavid V SchafferBACKGROUND:The pathologies of numerous retinal degenerative diseases can be attributed to a multitude of genetic factors, and individualized treatment options for afflicted patients are limited and cost-inefficient. In light of the shared neurodegenerative phenotype among these disorders, a safe and broad-based neuroprotective approach would be desirable to overcome these obstacles. As a result, gene delivery of secretable-neuroprotective factors to Müller cells, a type of retinal glia that contacts all classes of retinal neurons, represents an ideal approach to mediate protection of the entire retina through a simple and innocuous intraocular, or intravitreal, injection of an efficient vehicle such as an adeno-associated viral vector (AAV). Although several naturally occurring AAV variants have been isolated with a variety of tropisms, or cellular specificities, these vectors inefficiently infect Müller cells via intravitreal injection. METHODOLOGY/PRINCIPAL FINDINGS:We have previously applied directed evolution to create several novel AAV variants capable of efficient infection of both rat and human astrocytes through iterative selection of a panel of highly diverse AAV libraries. Here, in vivo and in vitro characterization of these isolated variants identifies a previously unreported AAV variant ShH10, closely related to AAV serotype 6 (AAV6), capable of efficient, selective Müller cell infection through intravitreal injection. Importantly, this new variant shows significantly improved transduction relative to AAV2 (>60%) and AAV6. CONCLUSIONS/SIGNIFICANCE:Our findings demonstrate that AAV is a highly versatile vector capable of powerful shifts in tropism from minor sequence changes. This isolated variant represents a new therapeutic vector to treat retinal degenerative diseases through secretion of neuroprotective factors from Müller cells as well as provides new opportunities to study their biological functions in the retina.http://europepmc.org/articles/PMC2758586?pdf=render |
| spellingShingle | Ryan R Klimczak James T Koerber Deniz Dalkara John G Flannery David V Schaffer A novel adeno-associated viral variant for efficient and selective intravitreal transduction of rat Müller cells. PLoS ONE |
| title | A novel adeno-associated viral variant for efficient and selective intravitreal transduction of rat Müller cells. |
| title_full | A novel adeno-associated viral variant for efficient and selective intravitreal transduction of rat Müller cells. |
| title_fullStr | A novel adeno-associated viral variant for efficient and selective intravitreal transduction of rat Müller cells. |
| title_full_unstemmed | A novel adeno-associated viral variant for efficient and selective intravitreal transduction of rat Müller cells. |
| title_short | A novel adeno-associated viral variant for efficient and selective intravitreal transduction of rat Müller cells. |
| title_sort | novel adeno associated viral variant for efficient and selective intravitreal transduction of rat muller cells |
| url | http://europepmc.org/articles/PMC2758586?pdf=render |
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