Novel AAV capsids for intravitreal gene therapy of photoreceptor disorders
Abstract Gene therapy using recombinant adeno‐associated virus (rAAV) vectors to treat blinding retinal dystrophies has become clinical reality. Therapeutically impactful targeting of photoreceptors still relies on subretinal vector delivery, which detaches the retina and harbours substantial risks...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2021-04-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202013392 |
| _version_ | 1797281824965132288 |
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| author | Marina Pavlou Christian Schön Laurence M Occelli Axel Rossi Nadja Meumann Ryan F Boyd Joshua T Bartoe Jakob Siedlecki Maximilian J Gerhardt Sabrina Babutzka Jacqueline Bogedein Johanna E Wagner Siegfried G Priglinger Martin Biel Simon M Petersen‐Jones Hildegard Büning Stylianos Michalakis |
| author_facet | Marina Pavlou Christian Schön Laurence M Occelli Axel Rossi Nadja Meumann Ryan F Boyd Joshua T Bartoe Jakob Siedlecki Maximilian J Gerhardt Sabrina Babutzka Jacqueline Bogedein Johanna E Wagner Siegfried G Priglinger Martin Biel Simon M Petersen‐Jones Hildegard Büning Stylianos Michalakis |
| author_sort | Marina Pavlou |
| collection | DOAJ |
| description | Abstract Gene therapy using recombinant adeno‐associated virus (rAAV) vectors to treat blinding retinal dystrophies has become clinical reality. Therapeutically impactful targeting of photoreceptors still relies on subretinal vector delivery, which detaches the retina and harbours substantial risks of collateral damage, often without achieving widespread photoreceptor transduction. Herein, we report the development of novel engineered rAAV vectors that enable efficient targeting of photoreceptors via less invasive intravitreal administration. A unique in vivo selection procedure was performed, where an AAV2‐based peptide‐display library was intravenously administered in mice, followed by isolation of vector DNA from target cells after only 24 h. This stringent selection yielded novel vectors, termed AAV2.GL and AAV2.NN, which mediate widespread and high‐level retinal transduction after intravitreal injection in mice, dogs and non‐human primates. Importantly, both vectors efficiently transduce photoreceptors in human retinal explant cultures. As proof‐of‐concept, intravitreal Cnga3 delivery using AAV2.GL lead to cone‐specific expression of Cnga3 protein and rescued photopic cone responses in the Cnga3−/− mouse model of achromatopsia. These novel rAAV vectors expand the clinical applicability of gene therapy for blinding human retinal dystrophies. |
| first_indexed | 2024-03-07T17:03:01Z |
| format | Article |
| id | doaj.art-8b6c55ffca62471b9aed7b84bf31bc23 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T17:03:01Z |
| publishDate | 2021-04-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-8b6c55ffca62471b9aed7b84bf31bc232024-03-03T03:16:35ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842021-04-01134n/an/a10.15252/emmm.202013392Novel AAV capsids for intravitreal gene therapy of photoreceptor disordersMarina Pavlou0Christian Schön1Laurence M Occelli2Axel Rossi3Nadja Meumann4Ryan F Boyd5Joshua T Bartoe6Jakob Siedlecki7Maximilian J Gerhardt8Sabrina Babutzka9Jacqueline Bogedein10Johanna E Wagner11Siegfried G Priglinger12Martin Biel13Simon M Petersen‐Jones14Hildegard Büning15Stylianos Michalakis16Department of Ophthalmology Ludwig‐Maximilians‐University Munich GermanyCentre for Integrated Protein Science Munich (CIPSM) at the Department of Pharmacy Ludwig‐Maximilians‐University Munich GermanyDepartment of Small Animal Clinical Sciences Michigan State University East Lansing MI USALaboratory for Infection Biology and Gene Transfer Institute of Experimental Haematology Hannover Medical School Hannover GermanyLaboratory for Infection Biology and Gene Transfer Institute of Experimental Haematology Hannover Medical School Hannover GermanyOphthalmology Services Charles River Laboratories Mattawan MI USAOphthalmology Services Charles River Laboratories Mattawan MI USADepartment of Ophthalmology Ludwig‐Maximilians‐University Munich GermanyDepartment of Ophthalmology Ludwig‐Maximilians‐University Munich GermanyDepartment of Ophthalmology Ludwig‐Maximilians‐University Munich GermanyDepartment of Ophthalmology Ludwig‐Maximilians‐University Munich GermanyCentre for Integrated Protein Science Munich (CIPSM) at the Department of Pharmacy Ludwig‐Maximilians‐University Munich GermanyDepartment of Ophthalmology Ludwig‐Maximilians‐University Munich GermanyCentre for Integrated Protein Science Munich (CIPSM) at the Department of Pharmacy Ludwig‐Maximilians‐University Munich GermanyDepartment of Small Animal Clinical Sciences Michigan State University East Lansing MI USALaboratory for Infection Biology and Gene Transfer Institute of Experimental Haematology Hannover Medical School Hannover GermanyDepartment of Ophthalmology Ludwig‐Maximilians‐University Munich GermanyAbstract Gene therapy using recombinant adeno‐associated virus (rAAV) vectors to treat blinding retinal dystrophies has become clinical reality. Therapeutically impactful targeting of photoreceptors still relies on subretinal vector delivery, which detaches the retina and harbours substantial risks of collateral damage, often without achieving widespread photoreceptor transduction. Herein, we report the development of novel engineered rAAV vectors that enable efficient targeting of photoreceptors via less invasive intravitreal administration. A unique in vivo selection procedure was performed, where an AAV2‐based peptide‐display library was intravenously administered in mice, followed by isolation of vector DNA from target cells after only 24 h. This stringent selection yielded novel vectors, termed AAV2.GL and AAV2.NN, which mediate widespread and high‐level retinal transduction after intravitreal injection in mice, dogs and non‐human primates. Importantly, both vectors efficiently transduce photoreceptors in human retinal explant cultures. As proof‐of‐concept, intravitreal Cnga3 delivery using AAV2.GL lead to cone‐specific expression of Cnga3 protein and rescued photopic cone responses in the Cnga3−/− mouse model of achromatopsia. These novel rAAV vectors expand the clinical applicability of gene therapy for blinding human retinal dystrophies.https://doi.org/10.15252/emmm.202013392achromatopsiaintravitreal deliverynovel AAVretina |
| spellingShingle | Marina Pavlou Christian Schön Laurence M Occelli Axel Rossi Nadja Meumann Ryan F Boyd Joshua T Bartoe Jakob Siedlecki Maximilian J Gerhardt Sabrina Babutzka Jacqueline Bogedein Johanna E Wagner Siegfried G Priglinger Martin Biel Simon M Petersen‐Jones Hildegard Büning Stylianos Michalakis Novel AAV capsids for intravitreal gene therapy of photoreceptor disorders EMBO Molecular Medicine achromatopsia intravitreal delivery novel AAV retina |
| title | Novel AAV capsids for intravitreal gene therapy of photoreceptor disorders |
| title_full | Novel AAV capsids for intravitreal gene therapy of photoreceptor disorders |
| title_fullStr | Novel AAV capsids for intravitreal gene therapy of photoreceptor disorders |
| title_full_unstemmed | Novel AAV capsids for intravitreal gene therapy of photoreceptor disorders |
| title_short | Novel AAV capsids for intravitreal gene therapy of photoreceptor disorders |
| title_sort | novel aav capsids for intravitreal gene therapy of photoreceptor disorders |
| topic | achromatopsia intravitreal delivery novel AAV retina |
| url | https://doi.org/10.15252/emmm.202013392 |
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