In-depth comparison of Anc80L65 and AAV9 retinal targeting and characterization of cross-reactivity to multiple AAV serotypes in humans
Anc80L65 is a synthetic, ancestral adeno-associated virus that has high tropism toward retinal photoreceptors after subretinal injection in mice and non-human primates. We characterized, for the first time, the post-intravitreal cell-specific transduction profile of Anc80L65 compared with AAV9. Here...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-09-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050123000785 |
| _version_ | 1797805829906235392 |
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| author | Maura K. Schwartz Shibi Likhite Tatyana A. Vetter Megan C. Baird Vicki McGovern Andrea Sierra Delgado Tom Mendel Arthur Burghes Kathrin C. Meyer |
| author_facet | Maura K. Schwartz Shibi Likhite Tatyana A. Vetter Megan C. Baird Vicki McGovern Andrea Sierra Delgado Tom Mendel Arthur Burghes Kathrin C. Meyer |
| author_sort | Maura K. Schwartz |
| collection | DOAJ |
| description | Anc80L65 is a synthetic, ancestral adeno-associated virus that has high tropism toward retinal photoreceptors after subretinal injection in mice and non-human primates. We characterized, for the first time, the post-intravitreal cell-specific transduction profile of Anc80L65 compared with AAV9. Here we use Anc80L65 and AAV9 to intravitreally deliver a copy of the gene encoding GFP into WT C57Bl/6J mice. GFP expression was driven by one of two clinically relevant promoters, chicken β actin (CB) or truncated MECP2 (P546). After qualitative assessment of relative GFP expression, we found Anc80L65 and AAV9 to have similar transduction profiles. Through the development of a novel method for quantifying GFP-positive retinal cells, we found Anc80L65 to have higher tropism in Müller glia and AAV9 to have higher tropism in horizontal cells. In addition, we found P546 to promote GFP expression at a more moderate level compared with the high levels seen under the CB promoter. Finally, for the first time, we characterized Anc80L65 cross-reactivity in human sera; 83% of patients with AAV2 pre-existing antibodies were found to be seropositive for Anc80L65. This study demonstrates the expanded therapeutic applications of Anc80L65 to treat retinal disease and provides the first insights to Anc80L65 pre-existing immunity in humans. |
| first_indexed | 2024-03-13T05:58:01Z |
| format | Article |
| id | doaj.art-74f44f3a86e0480ca1d2ed8f35f9aa98 |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-03-13T05:58:01Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-74f44f3a86e0480ca1d2ed8f35f9aa982023-06-13T04:12:10ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012023-09-01301629In-depth comparison of Anc80L65 and AAV9 retinal targeting and characterization of cross-reactivity to multiple AAV serotypes in humansMaura K. Schwartz0Shibi Likhite1Tatyana A. Vetter2Megan C. Baird3Vicki McGovern4Andrea Sierra Delgado5Tom Mendel6Arthur Burghes7Kathrin C. Meyer8The Center for Gene Therapy, Nationwide Children’s Hospital, Columbus, OH, USA; Biomedical Sciences Graduate Program, the Ohio State University, Columbus, OH, USAThe Center for Gene Therapy, Nationwide Children’s Hospital, Columbus, OH, USAThe Center for Gene Therapy, Nationwide Children’s Hospital, Columbus, OH, USA; Department of Pediatrics, the Ohio State University, Columbus, OH, USAThe Center for Gene Therapy, Nationwide Children’s Hospital, Columbus, OH, USA; Biomedical Sciences Graduate Program, the Ohio State University, Columbus, OH, USADepartment of Neurology, the Ohio State University, Columbus, OH, USAThe Center for Gene Therapy, Nationwide Children’s Hospital, Columbus, OH, USADepartment of Ophthalmology, the Ohio State University, Columbus, OH, USADepartment of Neurology, the Ohio State University, Columbus, OH, USAThe Center for Gene Therapy, Nationwide Children’s Hospital, Columbus, OH, USA; Biomedical Sciences Graduate Program, the Ohio State University, Columbus, OH, USA; Department of Pediatrics, the Ohio State University, Columbus, OH, USA; Corresponding author: Kathrin C. Meyer, PhD, The Center for Gene Therapy, The Research Institute, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205, USA.Anc80L65 is a synthetic, ancestral adeno-associated virus that has high tropism toward retinal photoreceptors after subretinal injection in mice and non-human primates. We characterized, for the first time, the post-intravitreal cell-specific transduction profile of Anc80L65 compared with AAV9. Here we use Anc80L65 and AAV9 to intravitreally deliver a copy of the gene encoding GFP into WT C57Bl/6J mice. GFP expression was driven by one of two clinically relevant promoters, chicken β actin (CB) or truncated MECP2 (P546). After qualitative assessment of relative GFP expression, we found Anc80L65 and AAV9 to have similar transduction profiles. Through the development of a novel method for quantifying GFP-positive retinal cells, we found Anc80L65 to have higher tropism in Müller glia and AAV9 to have higher tropism in horizontal cells. In addition, we found P546 to promote GFP expression at a more moderate level compared with the high levels seen under the CB promoter. Finally, for the first time, we characterized Anc80L65 cross-reactivity in human sera; 83% of patients with AAV2 pre-existing antibodies were found to be seropositive for Anc80L65. This study demonstrates the expanded therapeutic applications of Anc80L65 to treat retinal disease and provides the first insights to Anc80L65 pre-existing immunity in humans.http://www.sciencedirect.com/science/article/pii/S2329050123000785AAVintravitrealsubretinalretinatransductionimmunity |
| spellingShingle | Maura K. Schwartz Shibi Likhite Tatyana A. Vetter Megan C. Baird Vicki McGovern Andrea Sierra Delgado Tom Mendel Arthur Burghes Kathrin C. Meyer In-depth comparison of Anc80L65 and AAV9 retinal targeting and characterization of cross-reactivity to multiple AAV serotypes in humans Molecular Therapy: Methods & Clinical Development AAV intravitreal subretinal retina transduction immunity |
| title | In-depth comparison of Anc80L65 and AAV9 retinal targeting and characterization of cross-reactivity to multiple AAV serotypes in humans |
| title_full | In-depth comparison of Anc80L65 and AAV9 retinal targeting and characterization of cross-reactivity to multiple AAV serotypes in humans |
| title_fullStr | In-depth comparison of Anc80L65 and AAV9 retinal targeting and characterization of cross-reactivity to multiple AAV serotypes in humans |
| title_full_unstemmed | In-depth comparison of Anc80L65 and AAV9 retinal targeting and characterization of cross-reactivity to multiple AAV serotypes in humans |
| title_short | In-depth comparison of Anc80L65 and AAV9 retinal targeting and characterization of cross-reactivity to multiple AAV serotypes in humans |
| title_sort | in depth comparison of anc80l65 and aav9 retinal targeting and characterization of cross reactivity to multiple aav serotypes in humans |
| topic | AAV intravitreal subretinal retina transduction immunity |
| url | http://www.sciencedirect.com/science/article/pii/S2329050123000785 |
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